KR20210148318A - How to treat neuropathic pain - Google Patents

Abstract

The present invention relates to certain substituted heterocycle fused gamma-carbolines in free, solid, pharmaceutically acceptable salt and/or substantially pure form as described herein for use in a method for the treatment of neuropathic pain; to pharmaceutical compositions thereof.

Description

How to treat neuropathic pain

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is an international application claiming the priority and benefit of U.S. Provisional Application Serial No. 62/829,417, filed on April 4, 2019, the contents of which are incorporated herein by reference in their entirety.

Field of the Invention

The present invention relates to certain substituted heterocycle fused gamma-carbolines in free or pharmaceutically acceptable salt and/or substantially pure form as described herein, for the treatment and/or prophylaxis of neuropathic pain, to the use of the pharmaceutical composition.

Substituted heterocycle fused gamma-carbolines are known as agonists or antagonists of _{5-HT 2} receptors, particularly 5-HT _2A receptors, in the treatment of central nervous system disorders. Such compounds are disclosed in U.S. Patent Nos. 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282; _{Disorders associated with 5-HT 2A} receptor modulation in US RE39680, and US RE39679, such as obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual dysfunction, migraines, conditions associated with head pain, social phobias, gastrointestinal disorders such as , gastrointestinal motility disorders, and obesity. U.S. Pat. No. 8,309,722, and U.S. Pat. No. 7,081,455 also disclose methods for the preparation of substituted heterocycle fused gamma-carbolines and said gamma-carbolines as serotonin agonists and antagonists useful for the control and prevention of central nervous system disorders such as addictive behavior and sleep disorders. The use of carboline is disclosed.

Additionally, U.S. Pat. No. 8,598,119 discloses the use of certain substituted heterocycle fused gamma-carbolines for the treatment of psychotic and depressive disorders, as well as combinations of sleep, depression and/or mood disorders, in patients with psychosis or Parkinson's disease. initiating, and In addition to disorders associated with psychosis and/or depression, the present patent application relates to a high occupancy of _{the dopamine D 2} pathway by selectively antagonizing the _{5-HT 2A receptor, with no or minimal effect on the dopamine D2 receptor.} Side effects, or common sedative hypnotics (e.g., benzodiazepines), including, but not limited to, occurrence of drug dependence, decreased muscle tone, weakness, headache, blurred vision, dizziness, nausea, vomiting, epigastric discomfort, diarrhea, arthralgia, and chest pain ) and discloses and claims the use of the compounds of useful low doses for the treatment of sleep disorders without the side effects associated with other routes (e. g., GABA _a receptors). U.S. Patent No. 8,648,077 also discloses a process for preparing toluenesulfonic acid addition salt crystals of such substituted heterocycle fused gamma-carbolines.

Additionally, without being bound by theory, recent evidence suggests that some of the aforementioned substituted fused heterocyclic gamma carbolines act in a manner similar to ketamine, in part through NMDA receptor antagonism via mTOR1 signaling. show that you can Ketamine is a selective NMDA receptor antagonist. Ketamine works through a system unrelated to the usual psychogenic monoamines (serotonin, norepinephrine and dopamine), which is the main reason for its much faster effect. Ketamine directly antagonizes the extrasynaptic glutamate NMDA receptor, which also indirectly results in activation of the AMPA-type glutamate receptor. Downstream effects involve brain-derived neurotrophic factor (BDNF) and mTORC1 kinase pathways. Similar to ketamine, recent evidence suggests that compounds related to the compounds of the present disclosure enhance both NMDA and AMPA-induced currents in rat medial prefrontal cortical cone neurons through activation of the D1 receptor, which is associated with increased mTORC1 signaling. suggests that there is International application PCT/US2018/043100 (WO 2019/023062, the contents of which is incorporated herein by reference in its entirety) describes the above effects and useful therapeutic indications related thereto for certain substituted fused heterocycle gamma-carbolines. is disclosed, and there is.

US Patent 10,245260 discloses further novel fused heterocycle gamma-carbolines. This novel compound was found to exhibit serotonin receptor inhibition, SERT inhibition and dopamine receptor modulation. However, it has been unexpectedly discovered that this compound also exhibits significant activity at the mu-opiate receptor. Analogs of these novel compounds are also disclosed, for example, in publications WO 2018/126140, WO 2018/126143, and WO 2019/23063, the contents of which are incorporated herein by reference in their entirety. Among the indications disclosed in this publication are in general the treatment of pain, neuropathic pain, and chronic pain.

For example, the compounds of formula A shown below are potent serotonin 5-HT _2A receptor antagonists and mu-opiate receptor moieties, biased agonists. This compound also interacts with dopamine receptors, in particular the dopamine D1 receptor.

It is also believed that the compounds of formula (A) may enhance NMDA and AMPA-mediated signaling via the mTOR pathway through D1 receptor activity. Accordingly, the compounds of formula (A) are useful for the treatment or prevention of central nervous system disorders, including, for example, opiate addictions, such as opiate disorders.

Pain is the most common reason patients seek medical care. See The Merck Manual of Diagnosis and Therapy 1965-85 (Merck Sharpe & Dohme 2018). Acute pain, usually accompanying tissue damage, is caused by activation of peripheral pain receptors and their specific A delta and C sensory nerve fibers. Chronic pain due to persistent tissue damage is considered to result from chronic stimulation of these same sensory pathways. However, in the case of neuropathic pain, there is no peripheral tissue damage, and pain occurs due to damage or dysfunction of the nervous system itself (peripheral nerve or central nervous system).

Neuropathic pain may be based on underlying peripheral nerve damage or dysfunction. This includes, for example, carpal tunnel syndrome and mononeuropathy, such as neuromyopathy, eg, plexopathy, polyneuropathy, such as nerve compression due to a tumor or disc herniation. The mechanism of neuropathic pain is not yet well understood, but in some cases it may be related to an increase in the density of sodium channels in the regenerating nerve.

Neuropathic pain may also be based on an underlying central neuropathic pain syndrome. These are considered to involve reconfiguration of central somatosensory processing pathways, including afferent block pain and sympathetic maintenance pain. Afferent block pain results from partial or complete cessation of peripheral or central afferent nerve activity, such as postherpetic neuralgia, pain after central nervous system injury, and phantom limb pain (see after traumatic or nontraumatic [surgical] amputation). . Sympathetic maintenance pain is dependent on efferent sympathetic activity. Complex regional pain syndrome (CRPS) sometimes involves sympathetic maintenance pain. Mechanisms may include abnormal sympatho-somatic junctions (epaps), local inflammatory changes, and/or changes in the spinal cord.

Symptoms of neuropathic pain can vary, and include paresthesia (spontaneous or evoked burning pain, often superimposed with an oocyte component), hyperesthesia, allodynia (pain from previously innocuous stimuli), and hypersensitivity (particularly unpleasant, exaggerated pain response). Symptoms are long-lasting and, if associated with a primary cause (eg, acute injury), outlast resolution of the primary cause.

Current treatments for neuropathic pain have very limited success. Although several classes of drugs show some benefit, complete or near complete remission is not possible. Surprisingly, traditional analgesics, such as nonopioid analgesics (eg, nonsteroidal anti-inflammatory drugs, non-steroidal anti-inflammatory drugs) and opioid analgesics, lack significant efficacy or because the risk of addiction is too high (opioid analgesics). case), it is usually not prescribed. Instead, the drugs most frequently prescribed for neuropathic pain are antidepressants and anticonvulsants. Commonly prescribed antidepressants include amitriptyline, desipramine, and duloxetine. Commonly prescribed anticonvulsants include carbamazepine, gabapentin, phenytoin, pregabalin, and valproate. Each of these agents has different side effects and potential abuse potential.

Accordingly, there is a need for agents with improved ability to treat neuropathic pain with reduced potential for side effects.

Summary of the Invention

The present disclosure includes the step of administering to a patient in need of treatment for neuropathic pain a compound of formula (I): acceptable salt form), e.g., in isolated or purified free or salt form (e.g., in a pharmaceutically acceptable salt form), provides a method for treating neuropathic pain:

In the above formula,

R ¹ is H, C _{1- 6} alkyl, -C (O) -OC (R a) (R b) (R c), -C (O) -O-CH 2 -OC (R a) (R b )(R ^c ) or —C(R ⁶ )(R ⁷ )-OC(O)-R ⁸ ;

R ² and R ³ are independently selected from H, D, C _{1- 6} alkyl (e.g., methyl), C _{1- 6} alkoxy (e.g., methoxy), halo (e.g., F), cyano, or selected from hydroxy become;

L is C _{1- 6} alkylene (e.g., ethylene, propylene, or butylene), C _{1- 6} alkoxy (e. G., Propoxy or butoxy), C _{2- 3} alkoxy C _{1 - 3} alkylene group (e.g., CH _{2 CH 2 OCH 2), C} 1- 6 alkylamino or N- C _{1- 6} alkyl, C _{1- 6} alkylamino (e.g., propylamino, or N- methyl-propylamino), C _{1- 6} alkylthio (e. g., - _{CH 2 CH 2 CH 2 S-)} , C 1- 6 alkylsulfonyl _{(e.g., -CH 2 CH 2 CH 2 S} (O) 2 -) , and each of which is optionally substituted with one or more R ⁴ moiety;

Each R ⁴ is independently a C _{1- 6} alkyl (e.g., methyl), C _{1- 6} alkoxy (e.g., methoxy), halo (e.g., F), cyano, or is selected from hydroxy;

Z is selected from aryl (eg, phenyl) and heteroaryl (eg, pyridyl, indazolyl, benzimidazolyl, benzisoxazolyl), wherein said aryl or heteroaryl is optionally substituted with one or more R ⁴ moieties become;

R ⁸ is -C(R ^a )(R ^b )(R ^c ), -OC(R ^a )(R ^b )(R ^c ), or -N(R ^d )(R ^e );

R ^a, R ^b and R ^c are each independently selected from H and C _{1- 24} alkyl;

R ^d and R ^e is selected from each independently selected from H and C _{1- 24} alkyl;

R ⁶ and R ⁷ each independently is selected from H, C _{1- 6} alkyl, carboxy and C _{1- 6} alkoxycarbonyl.

In a further aspect, the present disclosure further provides the use of a compound of the present disclosure, such as a compound of Formula (I), in the manufacture of a medicament for the treatment of neuropathic pain. The present disclosure further provides a compound of the present disclosure, such as a compound of Formula (I), for use in the treatment of neuropathic pain.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the present disclosure provides a compound of formula I, or a pharmaceutical composition I, IA, IB, IC, comprising a compound of formula I, or any of P.1-P.7, wherein the compound of formula (I) is in free or salt form (eg, in a pharmaceutically acceptable salt form), eg, isolated or purified in its free or salt form (eg, in the form of a pharmaceutically acceptable salt);

wherein the pain is caused by a peripheral neuropathy (eg, mononeuropathy, plexopathy, neuromyopathy, or polyneuropathy) or a central neuropathy (eg, afferent block pain or sympathetic maintenance pain, such as complex Provided is a method (Method 1) of treating chronic pain and/or neuropathic pain caused by regional pain syndrome (CRPS):

In the above formula,

R ¹ is H, C _{1- 6} alkyl, -C (O) -OC (R a) (R b) (R c), -C (O) -O-CH 2 -OC (R a) (R b )(R ^c ) or —C(R ⁶ )(R ⁷ )-OC(O)-R ⁸ ;

R ² and R ³ are independently selected from H, D, C _{1- 6} alkyl (e.g., methyl), C _{1- 6} alkoxy (e.g., methoxy), halo (e.g., F), cyano, or selected from hydroxy become;

L is C _{1- 6} alkylene (e.g., ethylene, propylene, or butylene), C _{1- 6} alkoxy (e. G., Propoxy or butoxy), C _{2- 3} alkoxy C _{1 - 3} alkylene group (e.g., CH _{2 CH 2 OCH 2), C} 1- 6 alkylamino or N- C _{1- 6} alkyl, C _{1- 6} alkylamino (e.g., propylamino, or N- methyl-propylamino), C _{1- 6} alkylthio (e. g., - _{CH 2 CH 2 CH 2 S-)} , C 1- 6 alkylsulfonyl _{(e.g., -CH 2 CH 2 CH 2 S} (O) 2 -) , and each of which is optionally substituted with one or more R ⁴ moiety;

Each R ⁴ is independently a C _{1- 6} alkyl (e.g., methyl), C _{1- 6} alkoxy (e.g., methoxy), halo (e.g., F), cyano, or is selected from hydroxy;

Z is selected from aryl (eg, phenyl) and heteroaryl (eg, pyridyl, indazolyl, benzimidazolyl, benzisoxazolyl), wherein said aryl or heteroaryl is optionally substituted with one or more R ⁴ moieties become;

R ⁸ is -C(R ^a )(R ^b )(R ^c ), -OC(R ^a )(R ^b )(R ^c ), or -N(R ^d )(R ^e );

R ^a , R ^b and R ^c are each independently selected from _{H and C 1-24 alkyl;}

R ^d and R ^e are each independently selected from _{H and C 1-24 alkyl;}

R ⁶ and R ⁷ each independently is selected from H, C _{1- 6} alkyl, carboxy and C _{1- 6} alkoxycarbonyl.

The present disclosure provides a further exemplary embodiment method 1 comprising:

1.1 Method 1 comprising a compound of formula I, wherein ^{R 1 is H;}

1.2 R ¹ is C _{1- 6} alkyl, the method comprising a compound of the formula (I) is methyl 1;

1.3 Method 1 comprising a compound of formula I, wherein ^{R 1} is -C(O)-OC(R ^a )(R ^b )(R ^{c );}

1.4 R ^a is H, R ^b and R ^c are each independently a C _{1- 24} alkyl, C _{1- 20} alkyl, C ₂₀ alkyl, _{5-, 9-} C ₁₈ alkyl, C _{10- 16} alkyl, or C Method 1.3 comprising a compound of formula I, wherein said compound is selected from ₁₁ alkyl, C ₁₂ alkyl, C ₁₃ alkyl, C ₁₄ alkyl, C ₁₅ alkyl or C _{16 alkyl;}

1.5 and R ^a and R ^b is H, R ^c is a C _{1- 24} alkyl, C _{1- 20} alkyl, C ₂₀ alkyl, _{5-, 9-} C ₁₈ alkyl, C _{10- 16} alkyl, or C ₁₁ alkyl, Method 1.3 comprising a compound of formula I, wherein the compound is C ₁₂ alkyl, C ₁₃ alkyl, C ₁₄ alkyl, C ₁₅ alkyl or C _{16 alkyl;}

1.6 R ^a, R ^b and R ^c are each independently C _{1- 24} alkyl, C _{1- 20} alkyl, C ₂₀ alkyl, _{5-, 9-} C ₁₈ alkyl, C _{10- 16} alkyl, or C ₁₁ alkyl, Method 1.3 comprising a compound of formula I, wherein said compound is selected from C ₁₂ alkyl, C ₁₃ alkyl, C ₁₄ alkyl, C ₁₅ alkyl or C _{16 alkyl;}

1.7 Method 1.3 comprising a compound of formula I, wherein ^{R a , R b} and R ^{c are each H;}

1.8 and R ^a and R ^b is H, R ^c is a C _{10- 14} alkyl (e.g., R ^c is CH ₃ (CH _{2) 10} or CH ₃ (CH _{2) 14} a) comprises a compound of formula I to the How to do 1.3;

1.9 Method 1 comprising a compound of Formula I, wherein ^{R 1} is -C(O)-O-CH ₂ -OC(R ^a )(R ^b )(R ^{c );}

1.10 R ^a is H, R ^b and R ^c are each independently a C _{1- 24} alkyl, C _{1- 20} alkyl, C _5-20 alkyl, C _{9- 18} alkyl, C _{10- 16} alkyl, or C Method 1.9 comprising a compound of formula I, wherein said compound is selected from ₁₁ alkyl, C ₁₂ alkyl, C ₁₃ alkyl, C ₁₄ alkyl, C ₁₅ alkyl or C _{16 alkyl;}

1.11, and R ^a and R ^b is H, R ^c is a C _{1- 24} alkyl, C _{1- 20} alkyl, C ₂₀ alkyl, _{5-, 9-} C ₁₈ alkyl, C _{10- 16} alkyl, or C ₁₁ alkyl, Method 1.9 comprising a compound of formula I, wherein the compound is C ₁₂ alkyl, C ₁₃ alkyl, C ₁₄ alkyl, C ₁₅ alkyl or C _{16 alkyl;}

1.12 R ^a, R ^b and R ^c are each independently C _{1- 24} alkyl, C _{1- 20} alkyl, C _{5- 20} alkyl, C _9-18 alkyl, C _{10- 16} alkyl, or C ₁₁ alkyl, Method 1.9 comprising a compound of formula I, wherein said compound is selected from C ₁₂ alkyl, C ₁₃ alkyl, C ₁₄ alkyl, C ₁₅ alkyl or C _{16 alkyl;}

1.13 Method 1.9 comprising a compound of formula I, wherein ^{R a , R b} and R ^{c are each H;}

1.14 including compounds of formula I, wherein ^{R 1} is -C(R ⁶ )(R ⁷ )-OC(O)-R ^{8 and R 8} is -C(R ^a )(R ^b )(R ^{c )} How to do 1;

1.15 including compounds of formula I, wherein ^{R 1} is -C(R ⁶ )(R ⁷ )-OC(O)-R ^{8 and R 8} is -OC(R ^a )(R ^b )(R ^{c )} How to do 1;

1.16 R ^a is H, R ^b and R ^c are each independently a C _{1- 24} alkyl, C _{1- 20} alkyl, C ₂₀ alkyl, _{5-, 9-} C ₁₈ alkyl, C _{10- 16} alkyl, or C Method 1.14 or 1.15 comprising a compound of formula I, wherein said compound is selected from ₁₁ alkyl, C ₁₂ alkyl, C ₁₃ alkyl, C ₁₄ alkyl, C ₁₅ alkyl or C _{16 alkyl;}

1.17, and R ^a and R ^b is H, R ^c is a C _{1- 24} alkyl, C _{1- 20} alkyl, C ₂₀ alkyl, _{5-, 9-} C ₁₈ alkyl, C _10-16 alkyl or C ₁₁ alkyl, Method 1.14 or 1.15 comprising a compound of formula I, wherein the compound is C ₁₂ alkyl, C ₁₃ alkyl, C ₁₄ alkyl, C ₁₅ alkyl or C _{16 alkyl;}

1.18 R ^a, R ^b and R ^c are each independently C _{1- 24} alkyl, C _{1- 20} alkyl, C ₂₀ alkyl, _{5-, 9-} C ₁₈ alkyl, C _{10- 16} alkyl, or C ₁₁ alkyl, Method 1.14 or 1.15 comprising a compound of formula I, wherein said compound is selected from C ₁₂ alkyl, C ₁₃ alkyl, C ₁₄ alkyl, C ₁₅ alkyl or C _{16 alkyl;}

1.19 Method 1.14 or 1.15 comprising a compound of formula I, wherein ^{R a , R b} and R ^{c are each H;}

1.20, and R ⁶ is H, R ⁷ is C _{1- 3} alkyl (e.g., R ⁷ is methyl or isopropyl), R ⁸ is C _10-14 alkyl (eg R ⁸ is CH ₃ (CH ₂ ) ₁₀ or CH ₃ (CH ₂ ) ₁₄ ). -1.19 any of;

1.21 Method 1 comprising a compound of formula I, wherein ^{R 1} is -C(R ⁶ )(R ⁷ )-OC(O)-R ^{8 and R 8} is -N(R ^d )(R ^{e );}

1.22, and R ^d is H, R ^e are independently C _{1- 24} alkyl, C _{1- 20} alkyl, C _{5- 20} alkyl, C _{9- 18} alkyl, C _{10- 16} alkyl, or C ₁₁ alkyl, C Method 1.21 comprising a compound of formula I, wherein said compound is selected from ₁₂ alkyl, C ₁₃ alkyl, C ₁₄ alkyl, C ₁₅ alkyl or C _{16 alkyl;}

1.23 R ^d and R ^e are each independently C _{1- 24} alkyl, C _{1- 20} alkyl, C ₂₀ alkyl, _{5-, 9-} C ₁₈ alkyl, C _10-16 alkyl or C ₁₁ alkyl, C ₁₂ alkyl , C ₁₃ alkyl, C ₁₄ alkyl, C ₁₅ alkyl or C ₁₆ alkyl;

1.24 Method 1.21 comprising a compound of formula I, wherein ^{R d} and R ^{e are each H;}

1.25 any of Methods 1.14-1.24 comprising a compound of Formula I, ^{wherein R 6} is H and R ^{7 is H;}

1.26 R ⁶ is a C _{1- 6} alkyl, R ⁷ is any one of the methods that include the compounds of formula (I) 1.14 to 1.24 of C _{1- 6} alkyl;

1.27, and R ⁶ is H, R ⁷ is any one of the methods that include the compounds of formula (I) 1.14 to 1.24 of C _{1- 6} alkyl;

1.28 any of 1.14-1.24 comprising a compound of Formula I, ^{wherein R 6} is H and R ^{7 is carboxy;}

1.29 R ⁶ are H and, R ⁷ is C _{1- 6} alkoxycarbonyl, such as ethoxycarbonyl or methoxycarbonyl, including the method of carbonyl to compound of formula I by any of 1.14 to 1.24;

1.30 Method 1 comprising a compound of Formula I, or any of Methods 1.1-1.29, wherein ^{R 2} and R ^{3 are H;}

1.31 Method 1, or any of Methods 1.1-1.29, comprising a compound of Formula I, ^{wherein R 2} is H and R ^{3 is D;}

1.32 Method 1 comprising a compound of Formula I, or any of Methods 1.1-1.29, wherein ^{R 2} and R ^{3 are D;}

The 1.33 L are optionally substituted with one or more R ⁴ moiety, C _{1- 6} alkylene (e.g., ethylene, propylene, or butylene), C _{1- 6} alkoxy (e.g., propoxy), C _2- C ₃ alkoxy _{1 - 3} alkylene group _{(e.g., CH 2 CH 2 OCH 2)} C 1- 6 alkylamino (e.g., propylamino, or N- methyl-amino-propyl), or C _{1- 6} alkylthio (e.g., -CH ₂ CH ₂ CH ₂ S-) method 1, or any of methods 1.1-1.32;

1.34 how to L comprises a compound of formula I unsubstituted C _{1- 6} alkylene (e.g., ethylene, propylene, or butylene) to the 1.33;

1.35 how the L comprises a C _{1- 6} alkylene to a compound of formula I (for example, ethylene, propylene, or butylene), substituted with at least one R ⁴ moiety 1.33;

1.36 how to L comprises a compound of formula (I) is an unsubstituted C _{1- 6} alkoxy (e. G., Propoxy or butoxy) 1.33;

1.37 how the L comprises a C _{1- 6} alkoxy to compounds of Formula I (e. G., Propoxy or butoxy) substituted with at least one R ⁴ moiety 1.33;

1.38 L are unsubstituted C _{2- 3} alkoxy C _{1 -} comprises a compound of formula I ₃ alkylene (e.g., CH ₂ CH ₂ OCH ₂₎ to the 1.33;

1.39 The L is substituted with at least one R ⁴ moiety is C _{2- 3} alkoxy C _{1 - 3} alkylene group (e.g., CH ₂ CH ₂ OCH ₂₎ comprises a compound of formula I to the 1.33;

1.40 Method 1 comprising a compound of Formula I, wherein ^{R 1 , R 2} and R ³ are each H; or any of Methods 1.1-1.39;

1.41 L is - (CH _{2) n} -X-, wherein, n is an integer selected from 2, 3 and 4, X is -O-, -S-, -NH-, -N ( C 1- 6 method 1, or any of methods 1.1-1.40 comprising a compound of formula (I) selected from alkyl)-, and CH _{2 ;}

1.42 Method 1.41 comprising a compound of formula I, wherein L is -(CH ₂ ) _n -X-, wherein n is an integer selected from 2, 3 and 4 and X is -O-;

1.43 L is - (CH _{2) n} -X-, and, where, n is 3, X is -O-, -S-, -NH- and -N (C _{1- 6} alkyl) - (e.g., -N (CH ₃ )-) method 1.41 comprising a compound of formula (I);

1.44 Method 1.41 comprising a compound of Formula I, wherein L is -(CH ₂ ) _n -X-, wherein n is 3 and X is CH _{2 ;}

1.45 Method 1 comprising a compound of Formula I, or any of Methods 1.1-1.44, comprising a compound of Formula I wherein 1.45 Z is aryl (eg phenyl) optionally substituted with one or more R ^{4 moieties;}

1.46 Method 1.45 comprising a compound of Formula I, wherein Z is aryl (eg phenyl) substituted with one or more R ^{4 moieties;}

1.47 Method 1.46 comprising a compound of formula I, wherein Z is phenyl substituted with 1, 2, 3 or 4 R ^{4 moieties;}

1.48 Method 1.46 comprising a compound of Formula I, wherein 1, 2, 3 or 4 R ⁴ moieties are independently selected from halo (eg, fluoro, chloro, bromo or iodo) and cyano;

^{1.49 phenyl substituted with one R 4} moiety wherein Z is selected from halo (eg, fluoro, chloro, bromo or iodo) and cyano (eg, Z is 4-fluorophenyl, or 4-chlorophenyl , or 4-cyanophenyl); method 1.46 comprising a compound of formula I;

1.46 Method 1.46 comprising a compound of formula I, wherein Z is phenyl substituted with one fluoro (eg 2-fluorophenyl, 3-fluorophenyl or 4-fluorophenyl);

1.51 Method 1.46 comprising a compound of formula I, wherein Z is 4-fluorophenyl;

1.52 Method I, or method comprising a compound of Formula I, wherein Z is heteroaryl (eg eg pyridyl, indazolyl, benzimidazolyl, benzisoxazolyl) optionally substituted with one or more R ^{4 moieties} any of 1.1-1.44;

1.53 heteroaryl is a monocyclic 5 or 6 membered heteroaryl (eg, pyridyl, pyrimidyl, pyrazinyl, thiophenyl, pyrrolyl, thiophenyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, thia zolyl); method 1.52 comprising a compound of formula (I);

1.54 Method 1.53 comprising a compound of formula I, wherein the heteroaryl is selected from pyridyl, pyrimidanyl and pyrazinyl;

1.55 heteroaryl is a bicyclic 9-membered or 10-membered heteroaryl (eg, indolyl, isoindolyl, benzfuranyl, benzthiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthia method 1.52 comprising a compound of formula I, wherein the compound is zolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, benzodioxolyl, 2-oxo-tetrahydroquinolinyl;

1.56 Method 1.55 comprising a compound of formula I wherein the heteroaryl is selected from indazolyl, benzisoxazolyl, quinolinyl, benzodioxolyl, and 2-oxo-tetrahydroquinolinyl;

1.57 Method 1.55 comprising a compound of formula I, wherein the heteroaryl is selected from indazolyl, benzisoxazolyl, and quinolinyl;

1.58 any of Methods 1.52-1.57 comprising compounds of Formula I, wherein heteroaryl is substituted with 1, 2, 3 or 4 R ^{4 moieties;}

1.59 1, (as for example, fluoro, chloro, bromo or iodo), 2, 3 or 4 R ⁴ moiety is independently halo, cyano, hydroxy, or C _{1- 6} alkoxy (e.g., methoxy) 1.58 method comprising a compound of formula I, wherein said compound is selected from

^{1.60 heteroaryl is substituted with one R 4} moiety selected from halo (eg, fluoro, chloro, bromo or iodo) and cyano (eg, said heteroaryl is 6-fluoro-3- indazolyl, 6-chloro-3-indazolyl, 6-fluoro-3-benzisoxazolyl, or 5-chloro-3-benzisoxazolyl) method 1.58 or 1.59 comprising a compound of formula I;

1.61 Compounds are each independently

로 이루어진 군으로부터 선택되는 유리, 또는 약제학적으로 허용가능한 염 형태의 것인 화학식 I의 화합물을 포함하는 방법 1, 또는 1.1-1.60 중 임의의 것;

Method 1, or any of 1.1-1.60, comprising a compound of Formula I, in free, or pharmaceutically acceptable salt form, selected from the group consisting of;

1.62 Compounds are each independently

로 이루어진 군으로부터 선택되는 유리, 또는 약제학적으로 허용가능한 염 형태의 것인 화학식 I의 화합물을 포함하는 방법 1, 또는 1.1-1.60 중 임의의 것;

Method 1, or any of 1.1-1.60, comprising a compound of Formula I, in free, or pharmaceutically acceptable salt form, selected from the group consisting of;

1.63 Compounds are each independently

로 이루어진 군으로부터 선택되는 유리, 또는 약제학적으로 허용가능한 염 형태의 것인 화학식 I의 화합물을 포함하는 방법 1, 또는 1.1-1.60 중 임의의 것;

Method 1, or any of 1.1-1.60, comprising a compound of Formula I, in free, or pharmaceutically acceptable salt form, selected from the group consisting of;

인 것인 화학식 I의 화합물을 포함하는 방법 1, 또는 1.1-1.61 중 임의의 것;1.64 Compounds in free or pharmaceutically acceptable salt form

Method 1 comprising a compound of Formula I, or any of 1.1-1.61;

1.65 Method 1 comprising a compound of Formula I in free form, or any of 1.1-1.64;

1.66 Method 1, or any of 1.1-1.64 comprising a compound of Formula I in salt form, such as a pharmaceutically acceptable salt form;

1.67 Method 1, or any of 1.1-1.64, comprising a compound of Formula I, wherein the compound is in the form of an acid addition salt, eg, wherein the acid is hydrochloric acid or toluenesulfonic acid, glutamic acid, tartaric acid, malic acid or ascorbic acid;

1.68 Method 1, or any of 1.1-1.67, comprising the compound of Formula I in substantially pure diastereomeric form (ie, substantially free of other diastereomers);

1.69 Method 1 comprising a compound of formula I having a diastereomeric excess of greater than 70%, preferably greater than 80%, more preferably greater than 90%, and most preferably greater than 95%, or 1.1-1.67 any of;

1.70 Method 1 comprising a compound of Formula I in solid form, eg, crystalline form, or any of 1.1-1.69;

1.71 Method 1, or any of 1.1-1.70 comprising a compound of Formula I in isolated or purified form (eg, in at least 90% pure form, or in at least 95% or at least 98% or at least 99% pure form) thing;

1.72 Method 1, or any of 1.1-1.71, wherein the compound of formula (I) is administered in the form of a pharmaceutical composition comprising the compound of formula (I) in admixture with a pharmaceutically acceptable diluent or carrier;

1.73 Method 1.72, wherein the compound of formula I is administered in the form of a pharmaceutically acceptable salt admixed with a pharmaceutically acceptable diluent or carrier;

1.74 Method 1.72 or 1.73, wherein the pharmaceutical composition is a sustained release or delayed release formulation, eg, according to pharmaceutical composition 1-A as described herein;

1.75 method 1.72, 1.73 or 1.74, wherein the pharmaceutical composition comprises a compound of formula (I) in a polymer matrix, eg according to pharmaceutical composition 1-B as described herein;

1.76 any of methods 1.72-1.75, wherein the pharmaceutical composition is formulated as an osmotic controlled release oral delivery system, eg, according to pharmaceutical compositions 1-C or any of P.1 to P.7 as described herein. of one's;

1.77 any of Methods 1.72-1.76, wherein the pharmaceutical composition is in the form of a tablet or capsule;

1.78 any of Methods 1.72-1.77, wherein the pharmaceutical composition is formulated for oral, sublingual or buccal administration;

1.79 any of Methods 1.72-1.78, wherein the pharmaceutical composition is a fast-dissolving oral tablet (eg, a fast-dissolving sublingual tablet);

1.80 Methods 1.72-1.76 of any of Methods 1.72-1.76, wherein the pharmaceutical composition is formulated for intranasal or intrapulmonary administration (eg, as an aerosol, mist or powder for inhalation);

1.81 any of Methods 1.72-1.75, wherein the pharmaceutical composition is formulated for administration by injection, eg, as a sterile aqueous solution;

1.82 A method wherein the pharmaceutical composition is formulated for intravenous, intrathecal, intramuscular, subcutaneous or intraperitoneal injection 1.81.

As used herein, the term “compound of the present disclosure” refers to any compound described in Method 1 or a compound described in any of the embodiments 1.1 to 1.71.

In some embodiments, method 1 comprises administering a compound of the present disclosure in the form of a sustained or delayed release formulation (Pharmaceutical Composition 1-A), such as a depot formulation. In some embodiments, the compound of formula (I) or a compound as described in any of Methods 1.1-1.71, preferably in free or pharmaceutically acceptable salt form, admixed with a pharmaceutically acceptable diluent or carrier, It is provided in the form of an injectable depot, which provides for sustained or delayed release of the compound.

In certain embodiments, pharmaceutical composition 1-A comprises a compound of formula (I), or any compound of the present disclosure, in free base or pharmaceutically acceptable salt form, optionally in crystalline form, wherein the compound is micro Particle or nanoparticle size, such as a particle size by volume of 0.5 to 100 μm, for example, 5-30 μm, 10-20 μm, 20-100 μm, 20-50 μm or 30-50 μm (eg, diameter or Dv50) crushed or crystallized into particles or crystals. Such particles or crystals may be combined with an appropriate pharmaceutically acceptable diluent or carrier, eg, water, to form a depot for injection. For example, a depot formulation may be formulated for intramuscular or subcutaneous injection at a drug dosage suitable for a treatment of 4 to 6 weeks. In some embodiments, the particles or crystals have a surface area of 0.1 to 5 m 2 /g, such as 0.5 to 3.3 m 2 /g or 0.8 to 1.2 m 2 /g.

In another embodiment, the present disclosure provides pharmaceutical compositions I-B, wherein the compound of formula (I) (or any compound of the present disclosure) is pharmaceutical composition I in a polymer matrix. In one embodiment, a compound of the present disclosure is dispersed or dissolved within a polymer matrix. In a further embodiment, the polymer matrix comprises polyesters of hydroxyfatty acids and derivatives thereof, or alkyl alpha-cyanoacrylates, polyalkylene oxalates, polyortho esters, polycarbonates, polyortho carbonates, polyamino acids, hyaluronic acid standard polymers used in depot formulations, such as polymers selected from polymers of esters, and mixtures thereof. In a further embodiment, the polymer is polylactide, poly d,l-lactide, polyglycolide, or lactic acid to glycolic acid units in a ratio of 50:50 to 90:10 (eg, 50:50 to 75:25). PLGA, including any PLGA of In another embodiment, the polymer is poly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid, copolymers of said polymers, poly(aliphatic carboxylic acid), copolyoxalate, polycaprolactone, poly Albumins such as dioxanone, poly(ortho carbonate), poly(acetal), poly(lactic acid-caprolactone), polyorthoester, poly(glycolic acid-caprolactone), polyanhydride, and glycerol mono- and distearate , natural polymers including casein and wax, and the like. In a preferred embodiment, the polymer matrix comprises poly(d,l-lactide-co-glycolide).

Pharmaceutical Compositions I-B are particularly useful for sustained or delayed release, wherein the compound of the present disclosure is released upon degradation of the polymer matrix. These compositions may be formulated for controlled release and/or sustained release (e.g., as a depot composition) of a compound of the present disclosure over a period of up to 180 days, such as from about 14 days to about 30 days to about 180 days. . For example, the polymer matrix can degrade over a period of about 30 days, about 60 days, or about 90 days to release a compound of the present disclosure. In another example, the polymer matrix can degrade over a period of about 120 days or about 180 days to release a compound of the present disclosure.

In another embodiment, pharmaceutical compositions I, I-A or I-B may be formulated for administration by injection, eg, as a sterile aqueous solution.

In another embodiment, the present disclosure provides an osmotic controlled release oral delivery system (OROS) described in US 2001/0036472 and US 2009/0202631, the contents of each application being incorporated by reference in their entirety. system), provided herein is a pharmaceutical composition (pharmaceutical composition IC) comprising a compound of formula (I) (or any compound of the present disclosure) as described hereinabove. Thus, in one embodiment, the present disclosure relates to a pharmaceutical composition comprising (a) a gelatin capsule containing any compound of formula (I) in free or pharmaceutically acceptable salt form, optionally admixed with a pharmaceutically acceptable diluent or carrier; (b) a multilayer wall superimposed on the gelatin capsule comprising (i) a barrier layer, (ii) an expandable layer, and (iii) a semipermeable layer in an outward-facing order from the capsule; and (c) an orifice formed or capable of being formed through said wall (pharmaceutical composition P.1).

In another embodiment, the present invention provides a compound of formula (I) (or any compound of the present disclosure) in liquid, optionally admixed with a pharmaceutically acceptable diluent or carrier, in free or pharmaceutically acceptable salt form There is provided a pharmaceutical composition (pharmaceutical composition P.2) comprising a gelatin capsule containing It is surrounded by a composite wall comprising a semipermeable layer and an exit orifice formed or may be formed in the composite wall.

In yet another embodiment, the present invention provides a compound of formula I (or any compound of the present disclosure in free or pharmaceutically acceptable salt form, in liquid, optionally admixed with a pharmaceutically acceptable diluent or carrier. ) provides a composition (pharmaceutical composition P.3) comprising a gelatin capsule containing is surrounded by a composite wall comprising a semipermeable layer and an exit orifice formed or may be formed in the composite wall, wherein the barrier layer forms a seal between the intumescent layer and the exit orifice environment.

In yet a further embodiment, the present invention provides a compound of formula I (or any compound of the present disclosure in free or pharmaceutically acceptable salt form, in liquid, optionally admixed with a pharmaceutically acceptable diluent or carrier. ) provides a composition (pharmaceutical composition P.4) comprising a gelatin capsule comprising: a barrier layer in contact with the outer surface of the gelatin capsule, an expandable layer in contact with a portion of the barrier layer, at least an expandable layer is surrounded by a semi-permeable layer surrounding the capsule, and an exit orifice that is, or may be formed into, the dosage form that extends from the outer surface of the gelatin capsule to the environment of use. The expandable layer may be formed in one or more separate sections, such as, for example, two sections located on opposite sides or distal ends of the gelatin capsule.

In certain embodiments, a compound of the present disclosure (i.e., compositions P.1-P.4) in an osmotic controlled release oral delivery system is in a liquid formulation, wherein the formulation is a pure liquid active agent, solution, suspension, emulsion, or autologous formulation. It may be a liquid active agent in an emulsion composition, or the like.

gelatin capsules, barrier layers, expandable layers, semipermeable layers; and orifice features. Additional information on osmotic controlled release oral delivery systems can be found in US 2001/0036472, the content of which is incorporated by reference in its entirety.

Other osmotic controlled release oral delivery systems for compounds of formula (I) (or any compound of the present disclosure) or pharmaceutical compositions of the present disclosure are disclosed in US 2009/0202631, the content of which is incorporated by reference in its entirety. can be found in Therefore, in another embodiment, the present invention provides (a) two or more layers, wherein the two or more layers comprise a first layer and a second layer, wherein the first layer is a glass or a pharmaceutically acceptable salt. at least two layers comprising a compound of formula (I) and the following in the form, optionally in admixture with a pharmaceutically acceptable diluent or carrier, said second layer comprising a polymer; (b) an outer wall surrounding the at least two layers; and (c) an orifice in said outer wall (pharmaceutical composition P.5).

Pharmaceutical composition P.5 preferably employs a semi-permeable membrane surrounding a three-layered core; In these embodiments, the first layer is referred to as the first drug layer and contains a small amount of a drug (eg, a compound of Formula I and below) and an osmotic agent, such as a salt, and is referred to as a second drug layer. The middle layer contains a higher amount of drug, excipient, and no salt; The third layer, referred to as the push layer, contains an osmotic agent and no drug (Pharmaceutical composition P.6). At least one orifice is perforated through the membrane at the end of the first drug layer of the capsule tablet.

The pharmaceutical compositions P.5 or P.6 comprise a membrane defining a compartment, a membrane surrounding the inner protective subcoat, at least one exit orifice formed therein, or formable therein, and at least a portion of the membrane being semipermeable; an expandable layer located within the compartment remote from the outlet orifice and in fluid communication with the semipermeable portion of the membrane; a first drug layer positioned adjacent the exit orifice; and a drug layer comprising a compound of the present disclosure in free or pharmaceutically acceptable salt thereof, as a second drug layer located within the compartment between the first drug layer and the expandable layer (Pharmaceutical Composition P.7). . Depending on the relative viscosity between the first drug layer and the second drug layer, different release profiles are obtained. It is essential to identify the optimum viscosity for each layer. In the present invention, the viscosity is controlled by the addition of salt, sodium chloride. The delivery profile from the core is determined by the weight, formulation and thickness of each drug layer.

In certain embodiments, the present invention provides the pharmaceutical composition P.7, wherein the first drug layer comprises a salt and the second drug layer does not contain a salt. Pharmaceutical compositions P.5-P.7 may optionally include a flow promoting layer between the membrane and the drug layer.

Pharmaceutical compositions P.1-P.7 will generally be referred to as osmotic controlled release oral delivery system compositions.

In a further embodiment of the first aspect, the present disclosure provides a further embodiment of Method 1 wherein:

1.83 Method 1, or any of Methods 1.1-1.82, wherein the pain is chronic pain;

1.84 Method 1, or any of Methods 1.1-1.82, wherein the pain is neuropathic pain;

1.85 Methods 1.83 or 1.84, wherein the pain is chronic neuropathic pain.

1.86 Method 1, or method, wherein the pain is caused by a mononeuropathy (eg, mononeuropathy), such as focal mononeuropathy, pressure mononeuropathy, or sympathetic mononeuropathy (eg, carpal tunnel syndrome) any of 1.1-1.85;

1.87 Method 1, or any of Methods 1.1-1.85, wherein the pain is caused by a neuromyopathy, eg, caused by a herniated vertebral disc, or caused by diabetic ischemia;

1.88 Method 1, or any of Methods 1.1-1.85, wherein the pain is caused by a plexopathy, such as plexopathy caused by nerve compression, eg, nerve compression by a neuroma, tumor, or disc herniation;

1.89 Method 1, or any of Methods 1.1-1.85, wherein the pain is caused by a polyneuropathy or a polyneuropathy, such as diabetic polyneuropathy;

1.90 Method 1, or any of Methods 1.1-1.85, wherein the pain is caused by a central neuropathic pain syndrome, such as afferent block pain or complex regional pain syndrome (CRPS), or by fibromyalgia;

1.91 Method 1, or any of Methods 1.1-1.85, wherein the pain is caused by postherpetic neuralgia (PHN), or by fibromyalgia;

1.92 Pain is drug-induced neurotoxicity (e.g., doxorubicin, etoposide, gemcitabine, ifosfamide, interferon alpha, platinum chemotherapeutic agents (e.g., cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin, phenan) triplatin, picoplatin, satraplatin), or vinca alkaloids (eg, vinblastine, vincristine, vindesine, vinorelbine or vinpocetine), or antiretroviral nucleosides (eg, didanosine, stavudine) , induction by zalcitabine)), Method 1, or any of Methods 1.1-1.85;

1.93 any of Methods 1.83-1.92, wherein the neuropathy is an axonal neuropathy (ie, axonopathy);

1.94 Method 1, or any of Methods 1.1-1.93, wherein the patient has fibromyalgia, diabetes, human immunodeficiency virus (HIV) infection or acquired immune deficiency syndrome (AIDS), or cancer of one's;

1.95 Method 1, or any of Methods 1.1-1.93, wherein the patient is receiving concurrent treatment with, or has previously received treatment with, an antiretroviral nucleoside, a platinum-based antineoplastic agent, or a vinca alkaloid antineoplastic agent thing;

1.96 Method 1, or any of Methods 1.1-1.95, wherein the pain is associated with allodynia and/or hyperalgesia;

1.97 Patient has anxiety (including generalized anxiety, social anxiety and panic disorder), depression (eg, refractory depression and MDD), psychosis (including hallucinations or paranoid delusions of dementia-associated psychosis, eg, progressive Parkinson's disease), schizophrenia Method 1, or any of Methods 1.1-1.96, wherein the patient is suffering from an illness, migraine, substance abuse disorder, substance use disorder, opiate use disorder, or other drug dependence, such as stimulant dependence and/or alcohol dependence. of one's;

1.98 Method 1, or any of Methods 1.1-1.97, wherein the patient has been diagnosed with a substance use disorder or substance use disorder, such as an opiate use disorder (OUD);

1.99 The patient is prescribed an opioid or opioid drug such as morphine, codeine, thebaine, oripavine, morphine dipropionate, morphine dinicotinate, dihydrocodeine, buprenorphine, etorphine, hydrocodone, Hydromorphone, oxycodone, oxymorphone, fentanyl, alpha-methylfentanyl, alfentanil, trepanthinyl, brifentanil, remifentanil, octfentanil, sufentanil, carfentanil, meperidine, prodine, promedol, pro Foxyfen, dextropropoxyfen, methadone, diphenoxylate, dezosin, pentazocine, phenazosin, butorphanol, nalbuphine, levorphanol, levometorphan, tramadol, tapentadol, and anileridine; Method 1, or any of Methods 1.1-1.98, wherein the patient has a history of prior substance use or substance abuse for any combination thereof;

1.100 The patient is or has been diagnosed with opiate dependence, cocaine dependence, amphetamine dependence, and/or alcohol dependence, or is suffering from drug or alcohol dependence (e.g., opiate, cocaine, or amphetamine dependence) withdrawal Method 1, or any of Methods 1.1-1.99;

1.101 Method 1, or any of Methods 1.1-1.100, wherein the patient is a patient who has previously suffered from an opiate overdose;

1.102 Method 1, or any of Methods 1.1-1.100, wherein said method comprises administering to the patient an effective amount of a compound of formula (I);

1.103 effective amount is 1 mg-1000 mg, eg 2.5 mg-50 mg, or 25 mg-1500 mg, eg, 50 mg to 500 mg, or 250 mg to 1000 mg, or 250 mg for a long acting formulation. to 750 mg, or 75 mg to 300 mg;

1.104 method 1.103, wherein the effective amount is 1 mg-100 mg per day, such as 2.5 mg-60 mg per day, or 2.5 mg to 45 mg per day, or 5 mg to 25 mg per day;

1.105 the method of any one of the above methods, wherein the method further comprises co-administration of a selective serotonin reuptake inhibitor (SSRI), eg, concurrently, separately or sequentially;

1.106 Method 1.105, wherein the SSRI is selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline;

1.107 The method of any one of the above methods, wherein the method further comprises co-administration of a serotonin-norepinephrine reuptake inhibitor (SNRI), eg, concurrently, separately or sequentially;

1.108 Method 1.107, wherein the SNRI is selected from venlafaxine, sibutramine, duloxetine, atomoxetine, desvenlafaxine, milnacipran and levomynacipran;

1.109 The method of any one of the above methods, wherein the method further comprises co-administration of the antipsychotic agent, eg, concurrently, separately or sequentially;

1.110 Antipsychotics: Clomipramine, chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine, mesoridazine, molindone, perphenazine, pimozide, prochlorperazine, promazine, thioli selected from minced, thiothixene, trifluoperazine, brexpiprazole, cariprazine, asenapine, lurasidone, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone and paliperidone. Method 1.109;

1.111 the method of any one of the above methods, wherein the method further comprises co-administration of the NMDA receptor antagonist, eg, concurrently, separately or sequentially;

1.112 NMDA receptor antagonists include ketamine (eg, S-ketamine and/or R-ketamine), hydroxynorketamine, memantine, dextromethorphan, dextroalorphan, dextrorphan, amantadine and agmatine; or method 1.111 selected from the group consisting of any combination thereof;

1.113 of the methods above, wherein the method further comprises co-administration, eg, simultaneous, separate or sequential administration, of a compound that modulates GABA activity (eg, enhances activity and promotes GABA delivery). either method;

1.114 GABA modulating compounds are doxepin, alprazolam, bromazepam, clobazam, clonazepam, chlorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, tem selected from the group consisting of at least one of zepam, triazolam, indiflon, zopiclone, eszopiclone, zaleflon, zolpidem, gaboxadol, vigabatrin, tiagabine, EVT 201 (Evotec Pharmaceuticals) and estazolam 1.113;

1.115 The method of any one of the above methods, wherein the method further comprises co-administration of the 5-HT _{2A receptor antagonist, eg, concurrently, separately or sequentially;}

1.116 Said additional 5-HT _2A receptor antagonist is pimavanserine, ketanserine, risperidone, eplivanserine, volinanserin (Sanofi-Aventis, France), pruvanserine, MDL 100907 (Sanofi-Aventis, France) ), HY 10275 (EliLilly), APD 125 (Arena Pharmaceuticals, San Diego, CA) and AVE8488 (Sanofi-Aventis, France) method 1.115;

1.117 the method of any one of the above methods, wherein the method further comprises co-administration of a serotonin receptor antagonist/reuptake inhibitor (SARI), eg, concurrently, separately or sequentially;

1.118, Method 1.117, wherein the serotonin receptor antagonist/reuptake inhibitor (SARI) is selected from the group consisting of one or more of ritanserin, nefazodone, serzone and trazodone;

1.119 The method of any one of the preceding methods, wherein the method further comprises co-administration of the antidepressant, eg, concurrently, separately or sequentially;

1.120 Antidepressants amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, isocarboxa Zide, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine sulfate, protriptyline, sertraline, tranylcypromine, trazodone, trimipramine and venlafaxine Method 1.119;

1.121 The method of any one of the above methods, wherein the method further comprises co-administration of the opiate agonist or partial opiate agonist, eg, concurrently, separately or sequentially;

1.122 An opiate agonist or partial opiate agonist is a mu-agonist or partial agonist, or a kappa-agonist or partial agonist (mixed agonist/antagonist (e.g., partial mu-agonist activity and kappa-antagonist activity) method 1.121, including ));

1.123 Method 1.122, wherein the opiate agonist or partial agonist is buprenorphine, optionally wherein the method does not include co-treatment with an anxiolytic agent, such as a GABA compound or a benzodiazepine;

1.124 The method of any one of the above methods, wherein the method further comprises co-administration of the opiate receptor antagonist or inverse agonist, eg, concurrently, separately or sequentially;

1.125 The opiate receptor antagonist or inverse agonist is a complete opiate antagonist, e.g. selected from naloxone, naltrexone, nalmefene, methadone, nalorphine, levallorphan, samidorphan, nalodane, cyprodime or norbinaltorphimine In method 1.124.

1.126 The patient was previously treated with another pain-relieving drug and the patient did not respond adequately to the drug, e.g., the patient's pain was not sufficiently relieved, or the patient suffered from side effects that prevented continued treatment Method 1, or any of 1.1-1.125.

1.127 A method wherein the patient has developed or is at risk of developing an addiction to said other pain relief drug 1.126.

1.128 The other pain relief drugs are non-opiate analgesics (non-steroidal anti-inflammatory drugs such as ibuprofen, naproxen, ketoprofen, flurbiprofen, fenoprofen, oxaprozin, meclofenamate, mefenamic acid) , phenylbutazone, indomethacin, ketorolac, diclofenac, sulindac, etodolac, tolmethine, nabumetone, piroxicam, acetaminophen, aspirin, celecoxib, rofecoxib, valdecoxib, parecoxib, lum Lacoxib, etoricoxib, pyrocoxib), opiate analgesics (e.g. morphine, codeine, oxycodone, hydrocodone, hydromorphone, oxymorphone, buprenorphine, fentanyl, levorphanol, meperidine , nalbuphine, pentazocine, tramadol, methadone), and local anesthetics (such as benzocaine, lidocaine, procaine, bupivacaine, tetracaine) or other drugs (such as tricyclic antidepressants or anticonvulsants such as amitrip) tilin, desipramine, duloxetine, pregabalin, gabapentin, valproate, carbamazepine, phenytoin).

In another embodiment, the present disclosure provides that a compound of the present disclosure, or a pharmaceutical composition comprising the same, is administered over a period of about 14 days, about 30 to about 180 days, preferably about 30, about 60 or about 90 days. and the compound is administered in a controlled and/or sustained release form. Controlled and/or sustained release is particularly useful in avoiding premature discontinuation of treatment, particularly in antipsychotic drug therapy where non-compliance or non-compliance with drug therapy is common.

In some embodiments, the pain is caused by post-herpetic neuralgia. Postherpetic neuralgia (PHN) is a neuropathic pain caused by peripheral nerve damage caused by reactivation of the varicella zoster virus.

In some embodiments, the pain is caused by fibromyalgia, eg, the pain is a symptom of fibromyalgia. Fibromyalgia is a complex syndrome of uncertain cause or origin. It is classified as a pain processing disorder, particularly a pain signal processing disorder within the central nervous system. As such, it is similar to central neuropathic pain syndrome, and is often considered an example of 'central sensitization'. Fibromyalgia often includes allodynia and is characterized by chronic and widespread pain. In the United States, only pregabalin and duloxetine are approved for the management of fibromyalgia, and conventional analgesics are generally ineffective.

A patient suffering from a neuropathy that can be treated with opioid analgesics or other drugs with a high risk of abuse suffers from a substance use disorder or substance use disorder, or has a prior history of opioid addiction, opioid withdrawal, or opioid overdose; or if there is a previous case of substance abuse or alcohol abuse, the treatment will be contraindicated. Accordingly, there is a need for alternative non-addictive treatment methods, such as those described herein, especially for such patients.

Substance use disorders and substance-induced disorders are two categories of substance-related disorders defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). A substance use disorder is a pattern of symptoms that result from the use of a substance that an individual continues to take despite experiencing problems as a result of taking it. A substance-induced disorder is a disorder caused by the use of a substance. Substance-induced disorders include addiction, withdrawal, substance-induced mental disorders, including substance-induced psychosis, substance-induced bipolar disorder and related disorders, substance-induced depressive disorder, substance-induced anxiety disorder, substance-induced obsessive-compulsive disorder and related disorders, substance-induced sleep disorder, substance-induced induced sexual dysfunction, substance-induced delirium and substance-induced neurocognitive disorders.

DSM-5 contains criteria for classifying a substance use disorder as mild, moderate, or severe. In some embodiments of the methods disclosed herein, the substance use disorder is selected from a mild substance use disorder, a moderate substance use disorder, or a severe substance use disorder. In some embodiments, the substance use disorder is a mild substance use disorder. In some embodiments, the substance use disorder is a moderate substance use disorder. In some embodiments, the substance use disorder is a severe substance use disorder.

Anxiety and depression are very prevalent comorbid disorders in patients receiving treatment for substance use or substance abuse. A common treatment for substance abuse disorders is the combination of the partial opioid agonist buprenorphine and the opioid antagonist naloxone, but since none of these drugs have any significant effect on anxiety or depression, they usually take A third-party medication, such as an SSRI antidepressant, should also be prescribed. This makes the treatment regimen and patient compliance more difficult. In contrast, the compounds of the present disclosure provide opiate antagonism along with serotonin antagonism and dopamine modulation. This can lead to a significant improvement in the treatment of patients with substance use or abuse disorders who also present with anxiety and/or depression.

The compounds of the present disclosure may have anxiolytic properties that ameliorate the need to treat patients suffering from comorbid anxiety with anxiolytic agents. Accordingly, in some embodiments, the present disclosure provides a method according to method 1 et seq., wherein the patient is suffering from anxiety or anxiety symptoms, or is diagnosed with anxiety as a comorbid disorder or residual disorder, wherein the method comprises a benzodiazepine and the It does not include additional administration of anxiolytic agents such as other agents described in

In Method 1 and any embodiments below, wherein a compound of the present disclosure is administered in combination with one or more second therapeutic agents, the one or more second therapeutic agents may be administered as part of a pharmaceutical composition comprising a compound of the present disclosure. have. Alternatively, the one or more second therapeutic agents may be administered as separate pharmaceutical compositions (eg, pills, tablets, capsules, and injections) administered concurrently, sequentially or separately with administration of the compound of the present disclosure.

In a second aspect, the present disclosure provides a compound of the present disclosure, such as a compound of formula I or an embodiment of methods 1.1 to 1.71, in the manufacture of a medicament for use according to method 1 or any one of methods 1.1-1.128 Provided is the use of any of the compounds described in any of.

In a third aspect, the present disclosure describes a compound of the present disclosure, such as a compound of Formula I or any of the embodiments of Methods 1.1 to 1.71, for use according to Method 1 or any of Methods 1.1-1.128 any of the listed compounds.

Without wishing to be bound by theory, compounds of the present disclosure, such as compounds of Formula A, are potent 5-HT _2A , D ₁ and mu opiate modulators (eg, antagonists), which are also moderate D ₂ and SERT modulators (eg, for example, antagonism). It was also unexpectedly discovered that these compounds could act as "biased" mu opiate ligands. This means that when a compound binds to the mu opiate receptor, it can act as a partial mu agonist via G-protein coupled signaling, but as a mu antagonist via beta-arrestin signaling. This is in contrast to traditional opiate agonists such as morphine and fentanyl, which tend to strongly activate both G-protein signaling and beta-arrestin signaling. Activation of beta-arrestin signaling by these drugs is thought to mediate gastrointestinal dysfunction and respiratory depression normally mediated by opiate drugs. As a result, the compounds of the present disclosure, such as the compounds of formula (I), can therefore be expected to have a pain relief effect with less gastrointestinal and respiratory side effects than the conventional opiate analgesics. This effect has been shown in preclinical studies and in phase II and III clinical trials of the biased mu agonist oliseridine. Oliceridine has been shown to induce a biased mu agonist action via G-protein coupled signaling with reduced beta-arrestin signaling compared to morphine, which produces an analgesic effect with reduced respiratory side effects compared to morphine. related to the ability to Moreover, because these compounds antagonize the beta-arrestin pathway, they are expected to be useful in the treatment of opiate overdose because they will inhibit the most serious opiate side effects while still providing pain relief. Moreover, this compound also exhibits sleep maintenance effects due to its serotonin activity. As many people suffering from chronic pain have difficulty sleeping due to pain, these compounds can help these patients sleep at night due to the synergistic effect of serotonin and opiate receptor activity.

Accordingly, compounds of the present disclosure alone or in combination with opiate antagonists or inverse agonists (eg, naloxone or naltrexone) in patients suffering from opiate use disorder (OUD), opiate overdose or opiate withdrawal. effective for treating and/or preventing neuropathic pain in The compounds of the present disclosure are expected to provide potent analgesia without the side effects (eg, GI effects and decreased lung function) and the abuse potential seen with other opioid treatments (eg, oxycodone, methadone or buprenorphine). . The unique pharmacological profile of these compounds should also mitigate the risk of side effects of drug-drug interactions (eg alcohol). Accordingly, these compounds are particularly suited for long-term treatment and maintenance of pain in patients unable to take opioids or opioid drugs.

In some embodiments of the present disclosure, the compound of formula (I) has one or more biologically labile functional groups located within the compound such that its natural metabolic activity removes the labile functional group to yield another compound of formula (I). For example, R ¹ is C(O)-OC(R ^a )(R ^b )(R ^c ), -C(O)-O-CH ₂ -OC(R ^a )(R ^b )(R ^c ) or when -C(R ⁶ )(R ⁷ )-OC(O)-R ⁸ , the substituent is hydrolyzed under biological conditions ^{to yield the same compound in which R 1} is H, thus replacing the original compound with R ¹ It produces a prodrug of a compound that is H. Some of the above prodrug compounds have little or no biological activity, or only have moderate biological activity, but ^{upon hydrolysis to a compound in which R 1} is H, the compound may have potent biological activity. Thus, depending on the compound selected, administration of a compound of the present disclosure to a patient in need thereof induces an immediate biological and therapeutic effect, or an immediate, delayed biological and therapeutic effect, or only a delayed biological and therapeutic effect. can do. Accordingly, such prodrug compounds will serve as reservoirs of pharmacologically active compounds of formula (I ^{), wherein R 1 is H.} In this way, some compounds of the present disclosure are particularly suitable for formulation as long-acting injectable (LAI) or “depot” pharmaceutical compositions. Without wishing to be bound by theory, an injected "depot" comprising a compound of the present disclosure will progressively release the compound into a body tissue where the compound is progressively metabolized to form a compound of Formula I ^{wherein R 1 is H} compounds will be produced. Such depot formulations can be further adjusted by selection of appropriate ingredients to control the rate of dissolution and release of the compounds of the present disclosure. Such prodrug forms of compounds related to the compounds of formula (I) are disclosed, for example, in WO 2019/23063.

As used herein, “alkyl” is a saturated or unsaturated hydrocarbon moiety, eg, from 1 to 21 carbon atoms in length, unless otherwise specified, and any such alkyl, unless otherwise specified, is linear or minute. It may be topographic (eg n-butyl or tert-butyl), preferably linear. For example, “C _1-21 alkyl” refers to alkyl having 1 to 21 carbon atoms. In one embodiment, the alkyl is substituted with a group (for example ethoxy, a) one or more hydroxy or C _{1- 22} alkoxy, as appropriate. In another embodiment, the alkyl is preferably straight chain and optionally contains 1 to 21 carbon atoms, saturated or unsaturated, eg R ₁ is 1 to 21 carbon atoms, preferably 6 to 15 carbon atoms. A natural or unnatural, saturated or unsaturated fatty acid, e.g., together with -C(O)- to which it attaches when cleaved from a compound of Formula (I), in some embodiments that are carbon atoms, an alkyl chain containing 16 to 21 carbons. form a residue of

The term "pharmaceutically acceptable diluents or carriers" is intended to mean diluents and carriers that are useful in pharmaceutical preparations and are free of substances known to be allergenic, pyrogenic or pathogenic, and potentially disease-causing or promoting. do. Thus, a pharmaceutically acceptable diluent or carrier excludes body fluids such as blood, urine, spinal fluid, saliva, and the like, as well as its constituents such as blood cells and circulating proteins. Suitable pharmaceutically acceptable diluents and carriers can be found in any of several articles well known for pharmaceutical formulations, for example, Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics , Tenth Edition, McGraw Hill, 2001; [ Remington's Pharmaceutical Sciences , 20th Ed., Lippincott Williams & Wilkins., 2000]; and Martindale, The Extra Pharmacopoeia , Thirty-Second Edition (The Pharmaceutical Press, London, 1999), all of which are incorporated herein by reference in their entirety.

The term "purified", "purified form" or "isolated and purified form" for a compound refers to the physical state of the compound after it has been isolated from a synthetic process or natural source or combination thereof (e.g., from a reaction mixture) do. Thus, the terms “purified”, “purified form” or “isolated and purified form” for a compound refer to those described herein or by purification processes or processes well known to those of ordinary skill in the art (eg, chromatography, recrystallization, LC-MS and LC-MS/MS techniques, etc.), or refers to the physical state of the compound after it has been obtained in sufficient purity to be characterized by standard analytical techniques well known to those skilled in the art.

Unless otherwise specified, compounds of the present disclosure may exist in free base form or in salt form, eg, as a pharmaceutically acceptable salt form, eg, acid addition salt. A sufficiently basic salt of a compound of the present disclosure is an acid addition salt, such as an acid addition salt with an inorganic or organic acid, such as hydrochloric acid or toluenesulfonic acid. In addition, salts of the compounds of the present disclosure that are sufficiently acidic are alkali metal salts, such as sodium or potassium salts, or salts with organic bases that provide physiologically acceptable cations. In certain embodiments, the salt of a compound of the present disclosure is a toluenesulfonic acid addition salt.

The compounds of the present disclosure are for use as medicaments, and therefore pharmaceutically acceptable salts are preferred. Salts unsuitable for pharmaceutical use may be useful, for example, in the isolation or purification of free compounds of the present disclosure and are therefore also included within the scope of the compounds of the present disclosure.

The compounds of the present disclosure may contain one or more chiral carbon atoms. Accordingly, compounds exist as individual isomers, eg, in enantiomeric or diastereomeric forms, or as mixtures of individual forms, eg, racemic/diastereomeric mixtures. Any isomer may exist in which the asymmetric center is in the (R)-, (S)- or ( R,S )-configuration. It is to be understood that the present invention encompasses both the individual optically active isomers as well as mixtures thereof (eg racemic/diastereomeric mixtures). Thus, a compound of the present disclosure may be a racemic mixture, or may be predominantly, e.g., in pure, or substantially pure isomeric form, e.g., greater than 70% enantiomeric/diastereomeric excess ("ee") , preferably greater than 80% ee, more preferably greater than 90% ee, most preferably greater than 95% ee. Purification of the isomers and separation of the mixture of the isomers can be accomplished by standard techniques known in the art (eg, column chromatography, preparative TLC, preparative HPLC, simulated moving bed, etc.).

Geometric isomers depending on the nature of the substituents on the double bond or ring may exist in cis (Z ) or trans ( E ) form, and both isomeric forms are included within the scope of the present invention.

Also, the compounds of the present disclosure are intended to include stable and labile isotopes thereof. Stable isotopes are non-radioactive isotopes that contain one additional neutron compared to an abundant nuclide of the same species (ie, element). The activity of compounds containing such isotopes will be retained, and such compounds are also expected to have utility in determining the pharmacokinetics of non-isotopic analogs. For example, a hydrogen atom at a particular position on the compounds of the present disclosure may be replaced with deuterium (a stable isotope that is non-radioactive). Examples of known stable isotopes include, but are not limited to, ^{deuterium ( 2} H or D), ¹³ C, ¹⁵ N, ^{18 O. Alternatively, labile isotopes, such as 123} I, ¹³¹ I, ¹²⁵ I, ¹¹ C, ¹⁸ F, which are radioactive isotopes containing additional neutrons compared to abundant nuclides of the same species (i.e., elements), are It can replace abundant species of I, C and F. Another example of a useful isotope of a compound of the present disclosure is the ¹¹ C isotope. These radioisotopes are useful for radioimaging and/or pharmacokinetic studies of the compounds of the present disclosure. In addition, substitution of atoms of natural isotope distribution with heavier isotopes can result in desirable changes in pharmacokinetic rates when these substitutions are made at metabolically unstable sites. For example, ^{the incorporation of deuterium ( 2} H) in place of hydrogen can slow metabolic degradation when the hydrogen site is an enzyme or metabolically active site.

A compound of the present disclosure may be prepared as a depot formulation by, for example, dispersing, dissolving, suspending or encapsulating a compound of the present disclosure in a polymer matrix as described above such that the compound is continuously released as the polymer degrades over time. It can be administered in the form of a pharmaceutical composition. The release of a compound of the present disclosure from a polymer matrix can be, for example, controlled-and/or delayed of the compound from a pharmaceutical depot composition to a subject, e.g., a warm-blooded animal, e.g., a human, to which the pharmaceutical depot is administered. - and/or provides sustained-release. Thus, the medicament reservoir may contain a concentration of the present disclosure in a concentration effective to treat a particular disease or medical condition over a sustained period of time, e.g., 14-180 days, preferably over about 30 days, about 60 days or about 90 days. The compound is delivered to the subject.

Polymers useful for the polymer matrix in the compositions of the present disclosure (eg, depot compositions of the present disclosure) include polyesters of hydroxy fatty acids and derivatives thereof or other materials such as polylactic acid, polyglycolic acid, polycitric acid, poly Malic acid, poly-beta-hydroxybutyric acid, epsilon-capro-lactone ring-opened polymer, lactic acid-glycolic acid copolymer, 2-hydroxybutyric acid-glycolic acid copolymer, polylactic acid-polyethylene glycol copolymer or polyglycolic acid-polyethylene glycol Copolymers, polymers of alkyl alpha-cyanoacrylates (eg poly(butyl 2-cyanoacrylate)), polyalkylene oxalates (eg polytrimethylene oxalate or polytetramethylene oxalate), polyortho esters , polycarbonate (such as polyethylene carbonate or polyethylenepropylene carbonate), polyortho-carbonate, polyamino acids (such as poly-gamma-L-alanine, poly-gamma-benzyl-L-glutamic acid or poly-y-methyl-L- glutamic acid), hyaluronic acid esters, and the like, and one or more of these polymers may be used.

When the polymers are copolymers, they may be any random, block and/or graft copolymer. Since the alpha-hydroxycarboxylic acid, hydroxydicarboxylic acid and hydroxytricarboxylic acid have optical activity in the molecule, any one of the D-isomer, the L-isomer and/or the DL-isomer may be used. Among them, alpha-hydroxycarboxylic acid polymers (preferably lactic acid-glycolic acid polymers), esters thereof, poly-alpha-cyanoacrylic acid esters, etc. can be used, and lactic acid-glycolic acid copolymers (poly(lactide- alpha-glycolide) or poly(lactic-co-glycolic acid) (hereinafter referred to as PLGA). Accordingly, in one aspect, a useful polymer for the polymer matrix is PLGA. As used herein, the term PLGA includes polymers of lactic acid (also referred to as polylactide, poly(lactic acid), or PLA). Most preferably, the polymer is a biodegradable poly(d,l-lactide-co-glycolide) polymer.

In a preferred embodiment, the polymer matrix of the present disclosure is a biocompatible and biodegradable polymer material. The term "biocompatible" is defined as a polymeric material that is non-toxic, non-carcinogenic and does not significantly induce inflammation in body tissues. The matrix material must be biodegradable, where the polymer material must be broken down by bodily processes into products that the body can readily process, and must not accumulate in the body. The biodegradation product must also be biocompatible with the body in that the polymer matrix is biocompatible with the body. Particularly useful examples of polymer matrix materials are poly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid, copolymers thereof, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone, polydioxa Albumin, casein, such as non, poly(ortho carbonate), poly(acetal), poly(lactic acid-caprolactone), polyorthoester, poly(glycolic acid-caprolactone), polyanhydride, and glycerol mono- and distearate and natural polymers including waxes and the like. A preferred polymer for use in the practice of the present invention is dl (polylactide-co-glycolide). Preferably, the molar ratio of lactide to glycolide in such copolymers ranges from about 75:25 to 50:50.

Useful PLGA polymers may have a weight average molecular weight of about 5,000 to 500,000 Daltons, preferably about 150,000 Daltons. Depending on the rate of degradation achieved, polymers of different molecular weights may be used. For the diffusion mechanism of drug release, the polymer must remain intact until all drug has been released from the polymer matrix and then degraded. The drug may also be released from the polymer matrix as the polymer excipient erodes in vivo.

PLGA may be prepared by any conventional method or may be commercially available. For example, PLGA can be produced from cyclic lactide, glycolide, etc. by ring-opening polymerization using a suitable catalyst (see EP-0058481B2; Influence of polymerization parameters on PLGA properties: molecular weight, composition and chain structure).

PLGA is hydrolysable under biological conditions (e.g., in the presence of water and biological enzymes found in the tissues of warm-blooded animals such as humans) and is capable of degrading the entire solid polymer composition by breaking the enzymatically cleavable ester linkages. It is thought to be biodegradable to form lactic acid and glycolic acid. Both lactic acid and glycolic acid are water-soluble, non-toxic products of normal metabolism, which can further biodegrade to form carbon dioxide and water. In other words, PLGA is, for example, decomposed by hydrolysis of its ester group in the presence of water in the body of a warm-blooded animal such as man to produce lactic acid and glycolic acid, and to produce acidic microclimate I think. Lactic acid and glycolic acid are by-products of various metabolic pathways in the body of warm-blooded animals such as humans under normal physiological conditions and are therefore well tolerated and produce minimal systemic toxicity.

In another embodiment, the polymer matrix may comprise a star polymer in which the structure of the polyester is in the shape of a star. These polyesters have a single polyol moiety as a central moiety surrounded by a chain of acid moieties. The polyol moiety may be, for example, glucose or, for example, mannitol. These esters are known and are described in GB 2,145,422 and US Pat. No. 5,538,739, the contents of which are incorporated by reference.

Star polymers can be prepared using a polyhydroxy compound such as a polyol such as glucose or mannitol as an initiator. The polyol contains at least 3 hydroxy groups and has a molecular weight of about 20,000 daltons or less, for example, at least one, preferably at least two, eg, on average, three hydroxy groups of the polyol are of the ester groups. form and contain polylactide or co-polylactide chains. Branched polyesters such as poly(d,l-lactide-co-glycolide) have a central glucose moiety with a stem of linear polylactide chains.

A depot composition of the present disclosure as described above (eg, pharmaceutical composition IA or IB in a polymer matrix) comprises a polymer in microparticle or nanoparticulate or liquid form in which a compound of the present disclosure is dispersed or encapsulated therein. may include "Microparticle" means a solid particle containing a compound of the present disclosure in solution or solid form, wherein the compound is dispersed or dissolved in a polymer that acts as a matrix of particles. By appropriate selection of the polymeric material, microparticle formulations can be prepared in which the resulting microparticles exhibit both diffuse and biodegradable release properties.

When the polymer is in the form of microparticles, the microparticles may be prepared by any suitable method, for example, solvent evaporation or solvent extraction. For example, in a solvent evaporation method, the compounds and polymers of the present disclosure are mixed in a volatile organic solvent (eg, a ketone such as acetone, a halogenated hydrocarbon such as chloroform or methylene chloride, a halogenated aromatic hydrocarbon, a cyclic ether such as dioxane, ethyl esters such as acetate, nitriles such as acetonitrile, or alcohols such as ethanol) or dispersed in an aqueous phase containing a suitable emulsion stabilizer (eg polyvinyl alcohol, PVA). The organic solvent is then evaporated to provide microparticles encapsulated therein with a compound of the present disclosure. In solvent extraction methods, compounds and polymers of the present disclosure are dissolved in a polar solvent (eg, acetonitrile, dichloromethane, methanol, ethyl acetate or methyl formate) and then dispersed in an aqueous phase (eg, water/PVA solution). can be An emulsion is created to provide microparticles in which a compound of the present disclosure is encapsulated. Spray drying is an alternative manufacturing technique for making microparticles.

Other methods for making the microparticles of the present disclosure are also described in both US Pat. No. 4,389,330 and US Pat. No. 4,530,840.

Microparticles may be prepared by any method capable of producing microparticles of an acceptable size range for use in injectable compositions. One preferred method of preparation is the method described in US Pat. No. 4,389,330. In this method, the active agent is dissolved or dispersed in a suitable solvent. The polymeric matrix material is added to the medicament containing medium in an amount relative to the active ingredient that provides a product with the desired loading of active agent. Optionally, all components of the microparticle product may be blended together in a solvent medium.

Solvents for the compounds of the present disclosure and polymer matrix materials that may be used in the practice of the present disclosure include organic solvents such as acetone; halogenated hydrocarbons such as chloroform, methylene chloride and the like; aromatic hydrocarbon compounds; halogenated aromatic hydrocarbon compounds; cyclic ethers; alcohols such as benzyl alcohol; ethyl acetate and the like. In one embodiment, the solvent for use in the practice of the present disclosure may be a mixture of benzyl alcohol and ethyl acetate. Additional information on the preparation of microparticles useful in the present invention can be found in US Patent Application Publication No. 2008/0069885, which is incorporated herein by reference in its entirety.

The amount of compound of the present disclosure included in the microparticles generally ranges from about 1 wt.% to about 90 wt.%, preferably from 30 to 50 wt.%, more preferably from 35 to 40 wt.%. Weight percent means the portion of a compound of the present disclosure per total weight of microparticles.

Pharmaceutical depot compositions may include a pharmaceutically acceptable diluent or carrier, for example, a water-miscible diluent or carrier.

Details of osmotic controlled release oral delivery system compositions are found in EP 1 539 115 (US Patent Application Publication No. 2009/0202631) and WO2000/35419 (US 2001/0036472), each of which is incorporated herein by reference in its entirety. ) can be found.

An “effective amount” refers to a “therapeutically effective amount,” i.e., a compound of the present disclosure that, when administered to a subject suffering from a disease or disorder, is effective to cause reduction, alleviation, or regression of the disease or disorder over the period of time intended for treatment (e.g., contained in a pharmaceutical composition or dosage form).

The dosage used to practice the present invention will, of course, depend upon, for example, the particular disease or condition being treated, the particular compound of the present disclosure employed, the mode of administration, and the therapy desired. Unless otherwise indicated, an amount of a compound of the disclosure for administration (whether administered in free base or salt form) means or is based on (i.e., an amount of a compound of the disclosure in free base form). , the calculation of the amount is based on the amount of organic base).

The compounds of the present disclosure may be administered by any satisfactory route, including oral, parenteral (intravenous, intramuscular or subcutaneous) or transdermal. In certain embodiments, a compound of the present disclosure, eg, in a depot formulation, is preferably administered parenterally, eg, by injection, eg, by intramuscular or subcutaneous injection.

In general, satisfactory results for Method 1 and below as set forth above are about 1 mg to 100 mg once daily, preferably 2.5 mg to 50 mg once daily, eg 2.5 mg, 5 mg once daily. , obtained upon oral administration in doses of 10 mg, 20 mg, 30 mg, 40 mg or 50 mg.

For the treatment of a disorder disclosed herein wherein a longer duration of action is achieved using a depot composition, the dosage will be higher compared to the shorter acting composition, e.g., 1-100 mg, e.g., 25 mg, 50 mg, 100 mg, 500 mg, 1,000 mg, or greater than 1000 mg. The duration of action of the compounds of the present disclosure can be controlled by manipulation of the polymer composition, ie the polymer:drug ratio and microparticle size. When the composition of the present disclosure is a depot composition, administration by injection is preferred.

Pharmaceutically acceptable salts of compounds of the present disclosure can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid in water or an organic solvent, or a mixture of the two; In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Further details on the preparation of such salts, for example toluenesulfonic acid salts in amorphous or crystalline form, can be found in US 2011/112105.

Pharmaceutical compositions comprising a compound of the present disclosure can be prepared using conventional diluents or excipients (eg, including but not limited to, sesame oil) and techniques known in the galenic art. Accordingly, oral dosage forms may include tablets, capsules, solutions, suspensions, and the like.

The term "conjointly" when referring to therapeutic uses means that two or more active agents are administered to a patient as part of a regimen for the treatment of a disease or disorder, whether given the same or different times, or by the same or different routes of administration. means the administration of two or more active ingredients to Co-administration of two or more active ingredients may occur on the same day at different times, or on different days or at different frequencies.

The term "simultaneous" when referring to therapeutic use means the administration of two or more active ingredients simultaneously or nearly simultaneously by the same route of administration.

The term “individually” when referring to therapeutic uses means the administration of two or more active ingredients simultaneously or nearly simultaneously by different routes of administration.

Methods of making the compounds of the present disclosure :

Methods for the synthesis of compounds of formula (A), including the synthesis of intermediates used in the synthetic methods described below, have been disclosed, for example, in US Pat. No. 8,309,722, and US 2017/319580. Synthesis of similar fused gamma-carbolines is described, for example, in U.S. Pat. 8,309,722, U.S. 8,993,572, US 2017/0183350, WO 2018/126140 and WO 2018/126143, each of which is incorporated by reference in its entirety. Compounds of the present disclosure can be prepared using similar methods.

R ¹ is C(O)-OC(R ^a )(R ^b )(R ^c ), -C(O)-O-CH ₂ -OC(R ^a )(R ^b )(R ^c ) or -C( Compounds of formula I wherein R ⁶ )(R ⁷ )-OC(O)-R ⁸ can be prepared according to the methods disclosed in International Application PCT/US2018/043102.

Other compounds of the present disclosure can be prepared by methods analogous to methods known to those skilled in the art.

Isolation or purification of diastereomers of the compounds of the present disclosure is accomplished by conventional methods known in the art, for example, column purification, preparative thin layer chromatography, preparative HPLC, crystallization, trituration treatment, simulated moving bed, and the like. can be

Salts of the compounds of the present disclosure are disclosed in U.S. Patent Nos. 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282, 8,648,077; 9,199,995; 9,586,860; U.S. RE39680; and U.S. It may be prepared in a manner similar to that described in RE39679 (each of which is incorporated by reference in its entirety).

Diastereomers of the prepared compounds can be separated by HPLC using, for example, CHIRALPAK® AY-H, 5 μ, 30x250 mm at room temperature, eluted with 10% ethanol/90% hexanes/0.1% dimethylethylamine. can A peak can be detected at 230 nm to give a diastereomer of 98-99.9%ee.

Example

Example One: ( 6bR, 10aS )-8-(3-(4- Fluorophenoxy )profile)- 6b,7 ,8,9,10,10a- hexahydro Synthesis of -1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

(6bR,10aS)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[ 1,2,3-de]quinoxalin-2(3H)-one (100 mg, 0.436 mmol), 1-(3-chloropropoxy)-4-fluorobenzene (100 μl, 0.65 mmol) and iodine A mixture of potassium sulfide (KI) (144 mg, 0.87 mmol) was degassed with argon for 3 min and N,N -diisopropylethylamine (DIPEA) (150 μl, 0.87 mmol) was added. The resulting mixture was heated to 78° C. and stirred at that temperature for 2 h. The mixture was cooled to room temperature and then filtered. Purify the filter cake by silica gel column chromatography using a gradient of 0-100% ethyl acetate in a mixture of 7 N NH _{3 in methanol/methanol (1:0.1 v/v) as eluent to give the partially purified product} and it was further purified by semi-preparative HPLC system using a gradient of 0-60% acetonitrile in water containing 0.1% formic acid over 16 min to give the title product (50 mg, yield 30%) as a solid. did

Example 2: (6bR,10aS)-8-(3-(6-fluoro-1H-indazol-3-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido Synthesis of [3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

_{Step 1: To a stirred solution of BCl 3} .MeS (10.8 g, 60 mmol) in toluene at 0-5° C. 3-fluoroaniline (5.6 mL, 58 mmol) followed by 4-chlorobutyronitrile (7.12 g) 68.73 mmol) and aluminum chloride (AlCl ₃ ) (8.0 g, 60.01 mmol). The mixture was stirred at 130 °C overnight and cooled to 50 °C. Hydrochloric acid (3 N, 30 mL) was carefully added and the resulting solution was stirred at 90° C. overnight. The obtained brown solution was cooled to room temperature and evaporated to dryness. The residue was dissolved in dichloromethane (DCM) (20 mL) and basified to pH=7-8 with _{saturated Na 2} CO _{3 .} The organic phase was separated, _{dried over Na 2} CO ₃ and concentrated. The residue was purified by silica gel column chromatography using a gradient of 0-20% ethyl acetate in hexanes as eluent 2'-amino-4-chloro-4'-fluorobutyrophenone (3.5 g) as a yellow solid , yield 28%). MS (ESI) m/z 216.1 [M+1] ⁺ .

Step 2: To a suspension of 2'-amino-4-chloro-4'-fluorobutyrophenone (680 mg, 3.2 mmol) in concentrated HCl (14 mL) at 0-5° C. NaNO _{2 in water (3 mL)} (248 mg, 3.5 mmol) was added. The resulting brown solution was stirred at 0-5° C. for 1 h, then SnCl ₂ .2H ₂ O (1.74 g, 7.7 mmol) in concentrated HCl (3 mL) was added. The mixture was stirred at 0-5° C. for an additional 1 h, then dichloromethane (30 mL) was added. The reaction mixture was filtered and the filtrate was _{dried over K 2} CO ₃ and evaporated to dryness. The residue was purified by silica gel column chromatography using a gradient of 0-35% ethyl acetate in hexanes as eluent to 3-(3-chloropropyl)-6-fluoro- 1H -indazole as a white solid ( 400 mg, yield 60%) was obtained. MS (ESI) m/z 213.1 [M+1] ⁺ .

Step 3: (6bR,10aS)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] Quinoxalin-2(3H)-one (100 mg, 0.436 mmol), 3-(3-chloropropyl)-6-fluoro- 1H -indazole (124 mg, 0.65 mmol) and KI (144 mg, 0.87 mmol) ) was degassed with argon for 3 min, and DIPEA (150 μl, 0.87 mmol) was added. The resulting mixture was stirred at 78° C. for 2 h and then cooled to room temperature. The resulting precipitate was filtered. The filter cake was purified by a semi-preparative HPLC system using a gradient of 0-60% acetonitrile in water containing 0.1% formic acid over 16 min as an off-white solid (6bR,10aS)-8-(3-( 6-fluoro-1H-indazol-3-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[ 1,2,3-de]quinoxalin-2(3H)-one (50 mg, yield 28%) was obtained.

Example 3: (6bR,10aS)-8-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyri Synthesis of do[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

(6bR,10aS)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline- of 2(3H)-one (148 mg, 0.65 mmol), 3-(3-chloropropyl)-6-fluorobenzo[d]isoxazole (276 mg, 1.3 mmol) and KI (210 mg, 1.3 mmol) The mixture was degassed with argon and DIPEA (220 μl, 1.3 mmol) was added. The resulting mixture was stirred at 78° C. for 2 h and then cooled to room temperature. The mixture was concentrated in vacuo. The residue was suspended in dichloromethane (50 mL) and then washed with water (20 mL). The organic phase was _{dried over K 2} CO ₃ , filtered and then concentrated in vacuo. The crude product was subjected to silica gel column chromatography using a gradient of 0-10% methanol in ethyl acetate containing 1% 7 N NH _{3 to give the title product (80 mg, yield 30%) as a solid.}

Example 4: 4 -(3-(( 6bR, 10aS )-2-oxo-2,3, 6b,7 ,10,10a- hexahydro Synthesis of -1H-pyrido[3',4':4,5]-pyrrolo[1,2,3-de]quinoxalin-8(9H)-yl)propoxy)benzonitrile

Step 1: (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH) in dioxane (60 mL) A degassed suspension of -carboxylate (21.5 g, 66.2 mmol), chloroacetamide (9.3 g, 100 mmol), and KI (17.7 g, 107 mmol) was stirred at 104° C. for 48 h. The solvent was removed and the residue was suspended in dichloromethane (200 mL) and extracted with water (100 mL). The separated dichloromethane phase was _{dried over potassium carbonate (K 2} CO ₃ ) for 1 h and then filtered. Evaporation of the filtrate gave the crude product as a brown oil. To the brown oil was added ethyl acetate (100 m L) and the mixture was sonicated for 2 min. A yellow solid gradually precipitates out of the mixture, which turns into a gel upon standing at room temperature for a further 2 h. Additional ethyl acetate (10 mL) was added and the resulting solid was filtered. The filtered cake was washed with ethyl acetate (2 mL) and further dried under high vacuum to obtain (4aS,9bR)-ethyl 5-(2-amino-2-oxoethyl)-6-bromo-3,4, yields 4a and as an off-white solid (4aS,9bR)-ethyl 5-(2-amino-2-oxoethyl)-6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4 ,3-b]indole-2(9bH)-carboxylate (19 g, yield 75%)) was produced. This product was used directly in the next step without further purification. MS (ESI) m/z 382.0 [M+H] ⁺ .

Step 2: (4aS,9bR)-ethyl 5-(2-amino-2-oxoethyl)-6-bromo-3,4,4a,5-tetrahydro-1H-pyrido in dioxane (50 mL) A mixture of [4,3-b]indole-2(9bH)-carboxylate (12.9 g, 33.7 mmol), KI (10.6 g, 63.8 mmol), CuI (1.34 g, 6.74 mmol) was bubbled with argon for 5 min. ringed. To the mixture was added N,N,N,N'-tetramethylethylenediamine (3 mL), and the resulting suspension was stirred at 100° C. for 48 h. The reaction mixture was cooled to room temperature, poured onto a pad of silica gel and filtered. The filtered cake was washed with ethyl acetate (1 L x 2). The combined filtrates were concentrated to dryness and the product (6bR, 10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4 as a white solid. ,5]pyrrolo[1,2,3-de]quinoxaline-8-carboxylic acid ethyl ester (8 g, yield 79%) was obtained. MS (ESI) m/z 302.1 [M+H] ⁺ .

Step 3: (6bR, 10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1, 2,3-de]quinoxaline-8-carboxylic acid ethyl ester (6.4 g, 21.2 mmol) was suspended in HBr/acetic acid solution (64 mL, 33% w/w) at room temperature. The mixture was heated at 50° C. for 16 h. After cooling, treatment with ethyl acetate (300 mL), the mixture was filtered. The filter cake was washed with ethyl acetate (300 mL) and then dried under vacuum. The obtained HBr salt was then suspended in methanol (200 mL) and cooled with dry ice in isopropanol. With vigorous stirring, ammonia solution (10 mL, 7 N in methanol) was slowly added to the suspension to adjust the pH of the mixture to 10. The obtained mixture was dried under vacuum without further purification to obtain crude (6bR, 10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4' :4,5]pyrrolo[1,2,3-de]quinoxaline (8.0 g) was obtained, which was used directly in the next step. MS (ESI) m/z 230.2 [M+H] ⁺ .

Step 4: (6bR,10aS)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1, in DMF (2 mL) 2,3-de]quinoxalin-2(3H)-one (100 mg, 0.436 mmol), 4-(3-bromopropoxy)benzonitrile (99 mg, 0.40 mmol) and KI (97 mg, 0.44 mmol) ) was bubbled with argon for 3 min, and diisopropylethylamine (DIPEA) (80 μl, 0.44 mmol) was added. The resulting mixture was heated to 76° C. and stirred at that temperature for 2 h. The solvent was removed, and the residue was purified by silica gel column chromatography using a gradient of 0-100% mixed solvent [ethyl acetate/methanol/7 N NH ₃ (10:1: 0.1 v/v)] in ethyl acetate, The title product (35 mg, yield 45%) was obtained as a white foam.

Example 5: ( 6bR, 10aS )-8-(3-(4- chlorophenoxy )profile)- 6b,7 ,8,9,10,10a- hex Synthesis of hydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

(6bR,10aS)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo-[1,2, 3-de]quinoxalin-2 (3H) -one (110 mg, 0.48 mmol), 1- (3-bromopropoxy) -4-chlorobenzene (122 mg, 0.49 mmol) and KI (120 mg, 0.72) mmol) was added DIPEA (100 μl, 0.57 mmol). The resulting mixture was heated up to 76° C. and stirred at this temperature for 2 h. The solvent was removed, and the residue was purified by silica gel column chromatography using a gradient of 0-100% mixed solvent [ethyl acetate/methanol/7 N NH ₃ (10:1: 0.1 v/v)] in ethyl acetate, The title product (41 mg, yield 43%) was obtained as a white solid.

Example 6: ( 6bR, 10aS )-8-(3-(quinoline-8- Iloxy )profile)- 6b,7 ,8,9,10,10a- heck Synthesis of sahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

(6bR,10aS)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3 in DMF (2.5 mL) A mixture of -de]quinoxalin-2(3H)-one (120 mg, 0.52 mmol), 8-(3-chloropropoxy)quinoline (110 mg, 0.50 mmol) and KI (120 mg, 0.72 mmol) was added to 3 Bubbling with argon for min, DIPEA (100 μl, 0.57 mmol) was added. The resulting mixture was heated to a maximum of 76° C. and stirred at this temperature for 2 h. The solvent was removed and the residue was suspended in dichloromethane (30 mL) and washed with water (10 mL). The dichloromethane phase was dried _{over K 2} CO _{3 .} The separated organic phase was evaporated to dryness. The residue was purified by silica gel column chromatography using a gradient of 0-100% mixed solvent in ethyl acetate [ethyl acetate/methanol/7 N NH ₃ (10:1: 0.1 v/v)] to the title product as a light brown solid (56 mg, yield 55%) was obtained.

Example 7: Receptor binding profile

Receptor binding to the compound of Example 1 (compound of formula A) and the compounds of Examples 2 to 6 is determined. The procedures in the following documents are used, each reference being incorporated herein by reference in its entirety: 5-HT _{2A :} Bryant, HU et al. (1996), Life Sci ., 15:1259-1268]; D2: Hall, DA and Strange, PG (1997), Brit. J. Pharmacol ., 121:731-736]; D1: Zhou, QY et al. (1990), Nature, 347:76-80]; SERT: See Park, YM et al. (1999), Anal. Biochem ., 269:94-104]; Mu opiate receptor: Wang, JB et al. (1994), FEBS Lett ., 338:217-222].

In general, results are expressed as % control specific binding and % control specific binding inhibition obtained in the presence of the test compound as follows:

Control specific binding rate (%):

Control-specific binding inhibition (%):

.

.

IC ₅₀ values (concentrations causing half maximal inhibition of control-specific binding) and Hill coefficient (nH) were determined by nonlinear regression analysis of competition curves generated with mean replicate values using Hill equation curve fitting. do:

where Y = specific binding, A = left asymptote of curve, D = right asymptote of curve, C = compound concentration, C ₅₀ = IC ₅₀ , and nH = slope coefficient. This analysis was performed using self-developed software and confirmed by comparison with data generated by SigmaPlot® 40 (SPSS Inc, ⓒ1997) for commercial software Windows®. The inhibition constant (Ki) was calculated using the Cheng Prusoff equation:

where L = concentration of radioligand in the assay, K _D = affinity of radioligand for receptor. A Scatchard plot is used to determine _{K D .}

The following receptor affinity results are obtained:

Additional compounds of formula (I) are prepared by procedures analogous to those described in Examples 1-6. The receptor affinity results for these compounds are presented in the table below:

Example 8: in the mouse DOI judo head shaking model

R-(-)-2,5-dimethoxy-4-iodoamphetamine (DOI) is an agonist of the _{serotonin 5-HT 2 receptor family.} When administered to mice, a behavioral profile associated with frequent head shaking is generated. The frequency of these head shakes for a predetermined period of time can be considered as an estimate of _{5-HT 2 receptor agonism in the brain.} Conversely, this behavioral assay can be used to determine _{5-HT 2} receptor antagonism in the brain by administering a DOI in the presence or absence of the antagonist and recording the decrease in DOI-induced head shake following administration of the antagonist.

Darmani et al., Pharmacol Biochem Behav . (1990) 36:901-906] (the contents of which are incorporated by reference in their entirety) are used with some modifications. (±)-DOI HCl is injected subcutaneously and mice are immediately placed in a conventional plastic cage. The number of head shakes is counted for 6 min, starting from 1 min after DOI administration. Test compound is administered orally 0.5 hr prior to DOI injection. The results are calculated as EC50 for reducing DOI-induced head shake. The results are presented in the table below:

These results show that the compound of Example 1 potently blocks DOI head shake, which is consistent with the in _{vitro 5-HT 2A results presented in Example 7.}

Example 9: Mouse Tail Flick Assay

The mouse tail-flick assay is a measure of analgesia as indicated by the pain reflex threshold in controlled mice. The tail is heated by placing the male CD-1 mouse tail under a focused beam of high-intensity infrared heat source. The animal can withdraw its tail from the heat source at any time when it becomes uncomfortable. After turning on the heating device, record the time (delay time) until the mouse flicks its tail out of the path of the heat source. Administration of morphine produces analgesia, delaying the mouse's response to fever (increasing latency). Prior administration of a morphine receptor (MOR) antagonist, ie, naloxone (NAL), reverses this effect and induces a normal delay time. This test is used as a functional assay to determine the antagonism of the mu-opiate receptor.

Example 9a: Example Antagonism of morphine-induced analgesia by compound 1

Ten male CD-1 mice (approximately 8 weeks old) are assigned to each of the 5 treatment groups. Groups are treated as follows: Group (1) [Negative Control]: 0.25% methylcellulose vehicle p.o. 60 minutes before tail bouncing test, and saline vehicle 30 minutes before tail bouncing test; Group (2) [positive control]: 0.25% methylcellulose vehicle p.o. 60 minutes before the test, and 5 mg/kg morphine in saline 30 minutes before the test; Group (3) [positive control]: 3 mg/kg naloxone in saline 50 minutes before the test, and 5 mg/kg morphine in saline 30 minutes before the test; Groups (4) to (6): 0.1 mg/kg, 0.3 mg/kg or 1 mg/kg of test compound p.o. in 0.25% methylcellulose vehicle 60 minutes before the test, and 5 mg/kg morphine administration 30 minutes before the test. Results are presented in the table below as average delay times measured in seconds:

These results demonstrate that the compound of Example 1 exhibits a dose-dependent blockade of morphine-induced mu-opiate receptor activity.

Example 9b: in naloxone suppressed by Example analgesia by compound 1

In a second study using the mouse tail bouncing assay as described above, 1.0 mg of the compound of Example 1 was administered to morphine at 5 mg/kg with or without a pre-dosing (intraperitoneal) of naloxone at 3 mg/kg. Further comparisons are made at doses of /kg, 3.0 mg/kg and 10 mg/kg. In the pretreatment group, naloxone was administered 20 minutes before the tail bouncing test. In untreated controls, saline is administered 20 minutes prior to the tail bouncing test. In each group, vehicle, morphine or the compound of Example 1 is administered 30 minutes prior to the tail bouncing test. Results are presented in the table below as average delay times in seconds.

Administration of the compound of Example 1 at all doses significantly increased the delay time for tail bouncing, and this effect was found to be attenuated by pretreatment with naloxone. These results demonstrate the dose-dependent analgesic effect produced by the compound of Example 1 and further suggest that this effect is mediated by mu-opioid receptor agonism.

Example 9c: time course for analgesia, Example 1 compound

The tail bouncing assay as described above is repeated to determine the time course of analgesia due to administration of the compound of Example 1. Mice were given (1) vehicle 30 minutes before assay, (2) 5 mg/kg morphine 30 minutes before assay, or (3)-(7) 30 minutes, 2 hours, 4 hours, 8 hours or 24 hours before assay. 1 mg/kg of the compound of Example 3 sc dosing Results are presented in the table below as average delay times in seconds:

The results show that the compound of Example 1 produces effective analgesia when administered 30 minutes or 2 hours prior to the tail bouncing assay (ANOVA, P < 0.001 versus vehicle). When administered 4 hours, 8 hours, or 24 hours prior to the tail bouncing assay, 1 mg/kg of the compound of Example 1 does not produce an analgesic effect significantly different from the vehicle control. Thus, the compound of Example 1 does not produce prolonged analgesia, meaning that it has a lower abuse potential and a lower risk of drug-drug interactions compared to other opiate analgesics.

Example 9d: Example Pain due to chronic administration of compound 1

The tail bouncing assay as described above is repeated using the test model in which animals received acute treatment 30 min prior to tail bouncing assay after 14 days of chronic treatment regimen. Mice are divided into 3 broad groups with 6 subgroups of 10 mice each. Three groups receive (A) vehicle, (B) 0.3 mg/kg of compound of Example 1, or (C) 3.0 mg/kg of compound of Example 2 as chronic treatment. Each subgroup further receives (1) vehicle, or (2)-(6) 0.01, 0.03, 0.1, 0.3 or 1.0 mg/kg of the compound of Example 1 as acute treatment. All treatments are administered s.c. Results are presented in the table below as the average delay for tail bouncing in seconds:

It was found that 0.1, 0.3 and 1.0 mg/kg mg/kg acute treatment with the compound of Example 1 produced a statistically significant dose dependent analgesic effect compared to the within-group acute treatment with vehicle. This corresponds to the chronic groups (A), (B) and (C), respectively. Compared to pretreatment with vehicle, pretreatment with the compound of Example 1 at 0.3 mg/kg or 3.0 mg/kg generally showed a statistically significant decrease in tail bouncing delay time when comparing the same acute treatment subgroups. These results demonstrate that although some resistance to the analgesic effect of the compound of Example 1 develops after 14 days of chronic treatment, the obtained analgesia is still effective despite the chronic pretreatment.

Example 10: CNS phosphoprotein profile

A comprehensive molecular phosphorylation study is also performed to investigate the central nervous system (CNS) profile of the compound of Example 1. The degree of protein phosphorylation for selected major central nervous system proteins was measured in the mouse nucleus accumbens. The investigated proteins include ERK1, ERK2, Glu1, NR2B and TH (tyrosine hydroxylase), and the compound of Example 1 is compared with the antipsychotics risperidone and haloperidol.

Mice were treated with 3 mg/kg of the compound of Example 1 or 2 mg/kg of haloperidol. Mice were killed by focused microwave cranial irradiation 30 minutes to 2 hours after injection, which preserves brain phosphoproteins when present at the time of death. The cranial nuclei were then excised from each mouse brain, sliced, and frozen in liquid nitrogen. Zhu H, et al., Brain Res. 2010 Jun 25; 1342:11-23, samples were further prepared for phosphoprotein analysis via SDS-PAGE electrophoresis followed by phosphoprotein specific immunoblotting. Phosphorylation at each site was quantified, normalized to the total level of protein (non-phosphorylated), and expressed as a percentage of phosphorylation level in vehicle treated control mice.

The results show that in contrast to haloperidol, which gave a >400% increase in tyrosine hydroxylase phosphorylation, and risperidone, which resulted in >500% increase in tyrosine hydroxylase phosphorylation, the compound of Example 1 showed a positive response to TH phosphorylation at Ser40 at 30 min or 60 min. It is proven that there is no significant effect. This demonstrates that the compounds of the present invention do not interfere with dopamine metabolism.

The results further demonstrate that the compound of Example 1 did not significantly affect NR2B phosphorylation at Tyr1472 at 30-60 min. This compound resulted in a slight increase in GluR1 phosphorylation at Ser845 and a slight decrease in ERK2 phosphorylation at Thr183 and Tyr185. Protein phosphorylation at various sites within specific proteins is known to be associated with various activities of the cell, such as changes in protein transport, ion channel activity, synaptic signaling strength and gene expression. Phosphorylation of Tyr1472 at the NMDA glutamate receptor has been shown to be essential for the maintenance of neuropathic pain. Phosphorylation of Ser845 of the GluR1 AMPA-type glutamate receptor has been implicated in several aspects of the receptor's enhanced synaptic transmission and enhanced synaptic localization, supporting long-term potentiation related to cognitive ability. In addition, it has been reported that the channel opening potential increases due to phosphorylation of this residue. Phosphorylation of ERK2 kinase, a member of the MAP kinase cascade at residues T183 and Y185, is required for full activation of this kinase, and ERK2 is involved in various aspects of cell physiology including cell growth, survival and transcriptional regulation. This kinase has been reported to be important in synapse generation and cognitive function.

Example 11: Mu-opiate receptor activity assay

The compound of Example 1 is tested in CHO-K1 cells expressing hOP3 (human mu-opiate receptor μ1 subtype) using a HTRF-based cAMP assay kit (cAMP Dynamic2 Assay Kit, obtained from Cisbio, # 62AM4PEB). Frozen cells are thawed in a 37° C. water bath and resuspended in 10 mL of Ham F-12 medium containing 10% FBS. Cells were harvested by centrifugation and assay buffer (5 nM KCl supplemented with 1 mM IBMX, 1.25 mM MgSO ₄ , 124 mM NaCl, 25 mM HEPES, 13.3 mM glucose, 1.25 mM KH ₂ PO ₄ , 1.45 mM CaCl ₂ , 0.5 g/L protease-free BSA). The mu-opiate receptor partial agonist buprenorphine and the mu-opiate receptor antagonist naloxone, and the synthetic opioid peptide full agonist DAMGO serve as controls.

For the agonist assay, 12 μl of cell suspension (2500 cells/well) was mixed with 6 μl of poxsolin (10 μM final assay concentration) and, with increasing concentrations, 6 μl of test compound was added to a 384 well white plate. of the wells, and incubate the plate at room temperature for 30 min. Lysis buffer is added and, after an additional 1 hour incubation, the cAMP concentration is measured according to the kit instructions. All calibration points are measured in triplicate. Curve fitting is performed using XLfit software (IDBS) and EC ₅₀ values are determined using a 4-parameter logistic fit. An agonist assay measures the ability of a test compound to inhibit forskolin stimulated cAMP accumulation.

For the antagonist assay, 12 μl of cell suspension (2500 cells/well) is mixed with 6 μl of test compound in increasing concentrations, combined in wells of a 384 well white plate, and plates are incubated at room temperature for 10 minutes. incubate. 6 μl of a mixture of DAMGO (D-Ala ² -N- MePhe ⁴ -Gly-ol-enkepelin, 10 nM final assay concentration) and poxsolin (10 μM final assay concentration) was added, and the plate was incubated at room temperature for 30 min. incubate. Lysis buffer is added and, after an additional 1 hour incubation, the cAMP concentration is measured according to the kit instructions. All calibration points are measured in triplicate. Curve fitting is performed using XLfit software (IDBS) and IC ₅₀ values are determined using a 4-parameter logistic fit. The apparent dissociation constant (K _B ) is calculated using the modified Cheng-Prusov equation. The antagonist assay measures the ability of a test compound to reverse the inhibition of forskolin-induced cAMP accumulation induced by DAMGO.

The results are presented in the table below. The result is that the compound of Example 1 is _{a weak antagonist of the mu receptor, exhibiting a much higher IC 50} compared to naloxone, and only about 22 compared to DAMGO (compared to about 79% activity on buprenorphine compared to DAMGO). % agonist activity, showing a moderately high affinity, but partial agonist. The compound of Example 1 is also shown to have moderately strong partial agonist activity.

Although buprenorphine is a drug used for the treatment of chronic pain and for symptoms of opiate withdrawal, it suffers from the problem that users can become addicted due to its high partial agonist activity. To offset this, a commercial combination of buprenorphine and naloxone is used (sold as Suboxone). Without wishing to be bound by theory, a compound of the present invention that is a weaker partial mu agonist than buprenorphine, and has slightly moderate antagonistic activity, has a lower risk of intoxication in patients and is associated with pain and/or opiate withdrawal symptoms. It is thought to be effective for treatment.

In a further related study using the recombinant human MOP-beta-arrestin signaling pathway, the compound of Example 1 did not stimulate beta-arrestin signaling through the MOP receptor at concentrations up to 10 μM, but had an _{IC 50} It is confirmed to be an antagonist at 0.189 μM. In contrast, Met-enkephalin, a full opioid agonist, stimulates beta-arrestin signaling with _{an EC 50 of 0.08 μM.}

Example 12: rat Tolerance/dependency studies

The compound of Example 1 is evaluated during repeated daily (28 days) subcutaneous administration to male Sprague-Dawley rats to monitor drug effect on dosing and to determine if pharmacological tolerance develops. Additionally, the rats are monitored for behavioral, physical and physiological signs after abrupt cessation of repeated dosing to determine if the compound induces physical dependence on withdrawal. Additionally, pharmacokinetic studies are performed in parallel with resistance and dependence studies to determine plasma drug exposure levels of compounds at specific doses used in resistance and dependence studies. Morphine is used as a positive control and as a reference control from a similar pharmacological class to ensure the validity of the model.

The compound of Example 1 is evaluated at two doses of 0.3 and 3 mg/kg administered subcutaneously 4 times a day. Repeat dosing resulted in peak plasma concentrations of 15 to 38 ng/mL (mean, n = 3) for the 0.3 mg/kg dose, and 70 to 90 ng/mL (mean, n = 3) for the 3 mg/kg dose. was found to produce The peak concentration was reached 30 minutes to 1.5 hours after administration, and similar results were obtained on days 1, 14 and 28 of administration.

At both doses of the compound of Example 1, there was no significant effect on animal body weight, food and water intake or body temperature during dosing or during the withdrawal phase. The major behavioral and physical effects of repeated dosing of 0.3 mg/kg were found to be hunched posture, Straub tail and hair erection during the dosing phase. At high doses, the main behavioral and physical signs observed are hunched posture, calm behavior, straub tail, tail wag, and hair-up.

A similar profile of behavioral and physical signs is observed after abrupt discontinuation of the compound on study day 28. During the 0.3 mg/kg administration phase, no increase in hindfoot standing and body tone was observed, but a significant increase was confirmed during the withdrawal phase. At high doses, light hindpaw standing is observed during the administration phase, but more pronounced hindfoot standing and an increase in body tension are observed during the withdrawal phase.

As a positive control, morphine is administered orally at a dose of 30 mg/kg twice a day. As expected, this dosing regimen is observed to be associated with changes in body weight, food and water intake, rectal temperature and clinical signs consistent with the development of tolerance and withdrawal-induced dependence. Body weight increased significantly on days 2 and 3 compared to the vehicle-treated control group, whereas it decreased significantly from day 5. Morphine significantly reduced food intake on days 1-9. Thereafter, food intake was generally observed to be lower compared to the control group, but did not differ significantly from the control group on days 9, 13, 14 16, 18, 21, 22 and 25. These effects on body weight and food intake demonstrate resistance to the effects of morphine.

Water intake in the morphine-treated group was also significantly lower than in the control group on 25 of 28 days during the dosing phase. Body temperature is also generally lower than the control group during the dosing phase, and significantly lower on days 20, 21 and 27. The main behavioral effects induced by morphine during the dosing phase are observed to be Straub tails, jumping, digging, increased body tension, increased motor activity, explosive movements and eye bulging.

Additionally, withdrawal of morphine administration at day 28 results in an initial additional decrease in food intake followed by repulsive bulimia, and a significant increase in food intake is observed at day 33 compared to the control group. Feed intake returns to control levels by day 35. Similarly, it is also observed that rats previously receiving morphine exhibit an initial decrease in water intake on day 29 followed by repulsive thirst (water intake returns to control levels by day 31). Additionally, a statistically significant decrease in rectal body temperature is observed during dosing, but body temperature returns to control levels during the withdrawal phase.

In addition, new behavioral and physical signs are observed during the withdrawal phase from morphine, demonstrating the presence of dependence. These signs include piling, ataxia/staggering gait, wet dog shake, and abdominal twists. Other abnormal behaviors observed during the administration phase gradually disappear during the withdrawal phase. By day 35, hindpaw standing was the only behavioral or physical sign observed with a high incidence in rats previously receiving morphine.

Thus, repeated morphine administration appears to produce overt signs of tolerance and dependence in this study, with changes in body weight, food and water intake, rectal temperature and clinical signs consistent with the development of tolerance and withdrawal-induced dependence. This validates the study method for detecting physiological changes during dosing and discontinuation of dosing.

In contrast, four repeated administrations of the compound of Example 1 at both 0.3 and 3 mg/kg did not result in tolerance during subcutaneous administration for 28 days. Additionally, upon withdrawal, a similar but decreasing profile of behavioral and physical signs is observed at the highest dose, which is not considered clinically significant. Therefore, it was found that the compound of Example 1 did not cause the syndrome of physical dependence on discontinuation of administration as a whole.

Example 13: in the mouse oxycodone Study of dependence and withdrawal

Oxycodone was administered to males for 8 days in a dose escalation regimen (7 hours between injections) of 9, 17.8, 23.7, and 33 mg/kg bid on days 1-2, 3-4, 5-6, and 7-8, respectively. Administered to C57BL/6J mice. On the morning of day 9, mice are subcutaneously administered with the compound of Example 1 at 0.3, 1 or 3 mg/kg. Then, 30 minutes later, vehicle or 3 mg/kg of naloxone is injected. Another cohort of mice served as a negative control, and instead of oxycodone, these mice received saline from day 1 to day 8. On day 9, these mice received vehicle (followed by naloxone as above) or the compound of Example 1 at 3 mg/kg (followed by naloxone as above) s.c. dosing

On day 9, immediately after injection of naloxone (or vehicle), mice are individually placed in clear plastic cages and observed continuously for 30 minutes. Mice are monitored for common physical signs of opiate withdrawal, including jumping, wet dog brushing, paw tremors, gait, drooping eyelids, and diarrhea. All these behaviors are recorded as new onset when they are separated by at least 1 second, or when they cease to normal behavior. Animal body weights are also recorded immediately before naloxone (or vehicle) injection and 30 minutes after injection. After analyzing the data by ANOVA, a Tukey test for multiple comparisons is performed, if appropriate. The significance level is set to be p < 0.05.

The results are presented in the table below:

The total number of signs included tremors, jumps, and wet dog brushing. In oxycodone-treated mice, naloxone was found to induce a significant number of gross signs, paw tremors, jumping, and weight changes (p ≤ 0.0001, respectively). At all doses tested, the compound of Example 1 significantly reduced the total number of signs and foot tremors. In addition, at 3.0 mg/kg, the compound also induces a significant decrease in jumps and attenuation in weight loss.

These results demonstrate that the compound of Example 1 dose-dependently reduces the signs and symptoms of opiate withdrawal after abrupt cessation of opiate administration in opiate-dependent rats.

Example 14: Formalin Foot Test (Inflammatory Pain Model)

Subplantar administration of a chemical irritant such as formalin causes immediate pain and discomfort followed by inflammation in mice. Subcutaneous injection of a 2.5% formalin solution (37 wt% aqueous formaldehyde diluted in saline) into the hind paw results in a biphasic reaction of acute pain response and delayed inflammatory response. Thus, this animal model provides information for both acute pain and subacute/ankylosing pain in the same animal.

C57 mice are first tamed in the observation chamber. Thirty minutes prior to formalin administration, mice were given vehicle by subcutaneous injection, 5 mg/kg morphine (in saline) by subcutaneous injection, or 0.3, 1.0 or 3.0 mg/kg of the compound of Example 1 (45% w/v). in aqueous cyclodextrin) by subcutaneous injection. Additionally, another set of mice is treated with the control vehicle or the compound of Example 1 at 3.0 mg/kg via oral but not subcutaneous injection.

Then, the mice are subcutaneously injected with 20 μl of a 2.5% formalin solution into the plantar surface of the left hind paw. Then, over 40 minutes, the total time spent licking or biting the treated hind paw is recorded. The first 10 minutes indicate an acute nociceptive response, followed by a delayed inflammatory response of 30 minutes. At 1-minute intervals, each animal's behavior is assessed using the "Average Behavior Rating", which is scored on a scale from 0 to 4 as follows:

0: no response, sleeping animals,

1: treated paw, such as an animal that walks lightly on tiptoe,

2: Animals lifting treated paws,

3: Animal waving treated paws,

4: Animals licking or biting treated paws.

Data are analyzed by ANOVA, followed by post hoc comparisons by Fisher's test where appropriate. Significance is established with p < 0.05.

The results are presented in the table below.

The results demonstrate a significant therapeutic effect in both the early phase (0-10 min) and late phase (11-40 min) response periods. A post hoc comparison showed that subcutaneous injection of morphine or the compound of Example 1 (3 mg/kg) significantly attenuated the pain behavioral grade induced by formalin injection, as well as significantly reduced licking time compared to vehicle treatment. show Sikkim The post hoc comparison also shows that subcutaneous injection of morphine or the compound of Example 1 (3 mg/kg), and oral administration of the compound of Example 1 (3 mg/kg) significantly reduce the time spent licking. . Mean pain behavioral grades also decreased when using subcutaneous injection of compound at 1.0 mg/kg and oral administration of compound at 3.0 mg/kg, although this effect was not statistically significant in this study. Licking time was similarly reduced when subcutaneous injection of the compound of Example 1 at 1.0 mg/kg was administered, but the results were not statistically significant in this study. It was also confirmed that none of the mice in the study underwent significant body weight changes in any of the study groups.

Example 15: Heroin Maintenance in rats self-administration

A study was conducted to determine whether rats addicted to heroin self-administered the compound of Example 1 and found that they did not self-administer, further highlighting the non-addictive nature of the compounds of the present disclosure.

The study is carried out in three stages. In a first step, the rat is first trained to press the feeding lever, then the rat is trained to self-administer heroin by inserting an indwelling intravenous jugular vein catheter. In response to a stimulus (the light of an illumination in the cage), the animal presses the lever three times and heroin is injected once through the catheter. Heroin is given at an initial dose of 0.05 mg/kg/injection, then increased to 0.015 mg/kg/injection. This trained response is then quenched by replacing the heroin supply with saline. In a second step, the saline solution is administered at a dose of one of four doses of 0.0003 mg/kg/injection, 0.001 mg/kg/injection, 0.003 mg/kg/injection, and 0.010 mg/kg/injection of the compound of Example 1 replaced with a solution of Each individual rat is given one or two different doses of compound in a synergistic manner. This reaction is then quenched by saline injection, and then, in a third step, the use of 0.015 mg/kg/injection of heroin is repeated. The purpose of the third step is to demonstrate that the rats still exhibit addictive behavior to heroin at the end of the study. The study results are presented in the table below:

The results demonstrate that there is a statistically significant increase in lever press by rats when heroin is administered, but no significant difference when saline or the compound of Example 1 is administered. Thus, the results suggest that the rats are not addicted to the compound of Example 1.

It should be noted that, in this study, the term "recovery" is used to indicate that rats that were not interested in self-administering the compound of Example 1 will self-administer heroin if given. Thus, "recovery" herein means that the animal has maintained the ability or training to administer intravenous heroin on its own. However, the study results show that the rats did not choose to self-administer the compound of Example 1 in these circumstances, which does not psychologically reward the rats (ie, not psychologically addictive).

Example 16: of neuropathic pain rat Model

The compound of Example 1 is also tested in the STZ-rat model of neuropathic pain. Briefly, adult female rats are treated with streptozotocin (STZ), an alkylating neoplasm particularly toxic to insulin-producing beta cells of the pancreas, to develop diabetes. Type I diabetes produced in rats causes diabetic neuropathy over a period of 3-6 weeks. This can be demonstrated using various indicators of painful neuropathy, such as allodynia on light touch, hyperalgesia on pressure, cold heat and chemical stimulation. Once diabetic neuropathy is induced, mice can be treated to determine the analgesic effect of the compound.

The foot tactile response threshold is a clinical assessment of allodynia to light touch. Measurements can be made using a manual von Frey filament described in Otto et al., Pain, 101:187-92 (2003). A series of von Frey filaments with logarithmically increasing stiffness are used and the rat's response to each filament is observed. The results are used to calculate the 50%-retraction threshold (the degree of stiffness of the filament with a 50% probability that the rat's paw will recede).

The foot mechanical response threshold is also a clinical assessment of allodynia to light touch, but it depends on the observed response to pressure (force) applied to the foot.

The cold response threshold is a clinical assessment of cold pain perception. Stimulate the plantar surface of the hind paw for 5 seconds using a hard filament with a thermoelectric cooling system. Stimulation is repeated 10 times at intervals of 2 to 5 minutes. The number of paw withdrawal responses is recorded and converted to a number of response frequency (%). This procedure is repeated at various temperatures. It has been found that in diabetic rats, below a certain threshold temperature, an enhanced (hyperalgesic) response to cold is observed in rats. At stimulation temperatures of 20 °C or 15 °C, the response frequency was found to be substantially identical between STZ treated and control rats (approximately 10-20% response). In contrast, there is a significant difference in response frequency at stimulation temperatures below 10°C. In control rats, a stimulation temperature of 10° C. resulted in a response frequency of about 10%, whereas at 5° C. it increased to a response frequency of about 40%. In contrast, STZ-treated rats exhibit a response frequency of about 60% at 10°C and about 80% at 5°C. This shows that STZ-treated rats suffer from cold hyperalgesia at temperatures below 10°C. A stable allodynia response is observed 4-12 weeks after diabetes induction.

Example 16a: Example The compound of 1 is cold sore suppress the reaction.

Six groups of rats are compared for 6 hours after (subcutaneously) injection of the compound of Example 1 (“compound”) or vehicle: (1) control rats injected with vehicle, (2) 10 mg/kg of compound control rats injected, (3) STZ-diabetic rats injected with vehicle, (4) STZ-diabetic rats injected with 1 mg/kg compound, (5) STZ-diabetic rats injected with 3 mg/kg compound Rats and (6) STZ-diabetic rats injected with 10 mg/kg of compound. The cold allodynia reaction test was performed as described above using a stimulation temperature of 10° C. at 0 hours, 1 hour, 2 hours, 4 hours, and 6 hours. The injection vehicle is pure polyethylene glycol-400 (PEG400).

The results show that control rats (1) and (2) exhibit a response frequency of 10-30% at all time points (normal cold response). The positive vehicle control rats of group (3) always showed a response frequency of 70-90% and exhibited allodynia. Comparison of groups (4) and (6) shows a dose-dependent reduction in allodynia. At 1 mg/kg (group (4)), the compound decreased to a near-normal response frequency (~35% response) at 1 hour, which returned to about 70% at 4 hours and about 75% at 6 hours. decreases. At 3 mg/kg (group (5)), the compound reduced the response frequency to normal levels at 1 hour (about 10% response), which returned to about 65% at 4 hours and 75% at 6 hours. decreases. At 10 mg/kg (group (6)), the compound reduced the response frequency to the normal range (about 15%) at 1 hour, and the normal range at 2 hours and 4 hours (about 10% at 2 hours, 20%) at 4 hours, and rises to only about 40% at 6 hours.

Rats are also tested in a rotator cuff motor coordination model at a dose of 3 mg/kg, and no motor coordination resulting from the compound is found. This further demonstrates that the observation of allodynia was not due to a delayed motor response to a cold stimulus, but to pain suppression. Interestingly, the duration of action frame of subcutaneous injection of the compound is consistent with the results obtained in the mouse tail bouncing assay (Example 9c).

Example 16b: Example Compound 1 in response to tactile stimulation hyperalgesia restrain

Similar to the observations noted in Example 16a, STZ-treated diabetic rats exhibit stable tactile hyperalgesia as measured after manual application of von Frey filaments when tested 4-12 weeks after diabetes induction.

Rats are divided into 6 groups as described in Example 16a and monitored for 6 hours after administration of the compound of Example 1 or vehicle. This test is performed using von Frey filaments as described above.

The results show that control animals in group (1) and group (2) exhibit a 50% avoidance threshold of 8-14 g, which is within the normal range. In contrast, animals in the positive vehicle control group (3) exhibit a much lower 50% avoidance threshold of 2-3 g. Comparison of groups (4) and (6) shows a dose-dependent increase in the 50% avoidance threshold for the tactile stimulus. Consistent with the results of Example 16a, at a dose of 1 mg/kg, the compound moderately increases the threshold (peak threshold of about 4 g at 4 hours, dropping to about 3 g at 6 hours). At a dose of 3 mg/kg, the increase in the avoidance threshold increases to about 6 g at 1 hour, peaks at almost 8 g at 2 hours, and then drops to about 3 g at 4 hours. At a dose of 10 mg/kg, the increase in the avoidance threshold is much greater and reaches the range observed in control animals. Compound at 10 mg/kg produced a threshold of about 9 g at 1 hour, peaking at about 10 g at 2 hours, then at about 7 g at 4 hours, and at 6 hours. It drops to about 3 g.

Example 16c: Example Compound 1 responds to mechanical (pressure) stimuli. apperception suppress irritability

Rats are divided into 6 groups as described in Example 16a and monitored for 6 hours after administration of the compound of Example 1 or vehicle. This test is performed by measuring the static applied force threshold (pressure) for paw removal as described above.

The results show that both control animals in group (1) and group (2) exhibit an avoidance threshold of 55 to 70 g, which is within the normal range. In contrast, animals in the positive vehicle control group (3) exhibit a much lower avoidance threshold of 20-30 g. Comparison of groups (4) to (6) shows a dose-dependent increase in the avoidance threshold for mechanical stimulation. Consistent with the results of Examples 16a and 16b, at a dose of 1 mg/kg, the compound moderately increases the threshold (peak threshold of about 40 g at 4 hours, dropping to about 35 g at 6 hours). At the dose of 3 mg/kg, the increase in the avoidance threshold is greater, peaking at about 45 g at 2 hours but dropping to about 25 g at 6 hours. However, at the dose of 10 mg/kg, the increase in the avoidance threshold is much larger and more persistent, reaching the range observed in control animals. 10 mg/kg of compound produces a threshold of about 60 g at 1 hour, decreasing to 45-50 g at 2 to 4 hours, then dropping to about 35 g at 6 hours.

Example 17: Animal Pharmacokinetic Data

Using standard procedures, the pharmacokinetic profile of the compound of Example 1 is studied in several animals.

Example 17a: rat PK study

In a first study, rats were given the compound of Example 1 by intravenous bolus (IV) at 1 mg/kg in 45% Trapposol vehicle, or orally (10 mg/kg in 0.5% CMC vehicle). PO) (N=3 for each group). In a second study, rats were dosed with the compound of Example 1 at 10 mg/kg PO or 3 mg/kg subcutaneous (SC) in 45% Trapposol vehicle, respectively (N=6 for each group). The plasma concentration of the drug is measured at time points 0 to 48 hours after administration. Representative results are tabulated below (* indicates plasma concentrations below measurable levels of quantitation):

Example 17b: Mouse PK Study

A similar study was conducted using 10 mg/kg PO administration of the compound of Example 1 in mice and the following results were obtained: Tmax = 0.25 h; Cmax = 279 ng/mL; AUC (0-4 h) = 759 ng-hr/mL; The blood-plasma ratio (0.25-4 h) ranges from 3.7 to 6.6. The study is also conducted at a dose of 0.1 mg/kg SC. Representative results are presented in the table below:

These results collectively show that the compound of Example 1 is well absorbed and distributed in the brain and tissues, and is maintained with a fairly long half-life to allow once-daily administration of therapeutic doses.

Example 18: of neuropathic pain Zucker Fatty Diabetes rat Model

Insulin resistant diabetes occurs spontaneously in Zucker Fatty Diabetic (ZFD) rats. These rats show stable hyperglycemia and painful neuropathy that develops over several weeks. Painful neuropathy can be measured in rats using a variety of tests, including assays for paw tactile and pressure responses and thermal (cold) thresholds. Such trials could be used to determine the potential analgesic effect of a therapy under development.

In this experiment, the effect of the compound of Example 1 on pain threshold in ZFD-diabetic rats is evaluated. Formulated for subcutaneous (sc) or intrathecal (it) administration in 10% Trappsol (beta-cyclodextrin) in water with the addition of 1% Tween-80 to the compound of Example 1 to form a clear solution do.

Forty adult male Sprague-Dawleys weighing 225-275 g at the start of the study, including 10 lean control and 30 ZFD rats, are used in this experiment. Animals are maintained in the cage daily under fluorescent lighting on a 12 hour light/dark cycle at a controlled room temperature of 65-85°F and a relative humidity of 30-70%. All animals are kept two per cage with free access to dry food and water.

Insulin resistant diabetes can develop in male ZFD rats. Hypoglycemia is confirmed after 4 days in blood samples obtained by tail sting using a strip-actuated reflexometer, and is also confirmed at death. All animals are observed daily for the duration of the study. Body weight and plasma glucose levels are measured at the end of the study.

Foot Tactile Response Threshold: This trial repeats the clinical assessment of allodynia on light touch detected using von Frey filaments, and a standard assay for the detection of allodynia occurring within 2-4 weeks of the onset of diabetes in ZFD-diabetic rats. acts as Current methods are described in detail in Calcutt, NC, Modeling Diabetic Sensory Neuropathy in Rats, Methods in Molecular Medicine 99: 55-65 (2004).

Foot Pressure Response Threshold: This test applies greater force to the plantar hindfoot than manual von Frey filaments, and can be equivalent to pressure-induced pain as described by diabetic subjects when standing or walking. Hyperalgesia for this measure develops over several weeks in ZFD rats, allowing this test to provide an assessment of allodynia and other hyperalgesia and drug efficacy measured with passive von Frey filaments. This method is described in detail in Lee-Kubil, Mixcoati-Zecuatl, Jolivalt, & Calcutt, Animal Models of Diabetes-Induced Neuropathic Pain , Current Topics in Behavioral Neurosciences 20: 147-170 (2014).

Cold Response Threshold: This trial repeats the clinical trial of Cold Pain Perception Threshold. The rats are transferred to a test cage with a wire mesh bottom and allowed to acclimate. Stimulate the plantar surface of the hind paw for 5 s using a hard filament attached to a Peltier thermoelectric cooling system. Stimulation is repeated 10 times at intervals of 2 to 5 minutes, and the number of foot avoidance responses is recorded and converted into response frequency (%). This paradigm is repeated at various stimulation temperatures. ZFD diabetic rats develop cold hyperalgesia at temperatures below 10°C, but the normal response frequency at higher temperatures confirms that they do not show an exaggerated response to the applied pressure itself (see Table 18-1 below). .

Foot Formalin Test: This test allows the distinction of primary afferent input (stage 1) versus pain induced by spinal sensitization and amplification of primary afferent input (stage 2). However, there is no clinical trial equivalent to this trial. The method used here is described in detail in Calcutt (2004), supra.

dosing procedure. Zucker fatty diabetic rats were shown to develop hyperglycemia over 6-8 weeks. After confirmation of hyperglycemia, rats are tested weekly until baseline measurements indicate stable development of allodynia/hyperalgesia (3-6 weeks diabetes). When the presence of painful neuropathy is confirmed, the rats are tested for three measures of hyperalgesia: allodynia threshold, tactile hyperalgesia (von Frey filaments) and pressure response as measured by a mechanical von Frey apparatus. All rats are tested in three assay assays, and all rats receive each of the four pretreatments administered subcutaneously (s.c.) in a vehicle of 10% Trapsol in water. All rats receive treatment in the same sequence as follows: vehicle, 1 mg/kg Ex. Compound 1, 3 mg/kg Ex. 1, and 10 mg/kg Ex. 1 compound. Rats receive a pretreatment 30 minutes prior to the start of the test. Hyperalgesia/allodynia measurements are recorded from each rat at baseline (hour 0), then 1, 2, 3, 4, and 6 h post treatment.

After completion of testing on all rats at all doses/conditions for each assay (cold, tactile and pressure response), rats were administered vehicle or Ex. A cannula for intrathecal (i.t.) application of compound 1 (1, 3 or 10 μg) is mounted and administered directly to the spinal cord. All rats are then retested in each tree assay in each of the four pretreatment conditions/dose.

Statistical analysis. s.c. Allodynia test data with dosing are analyzed using MANOVA for repeated measures over time and baseline for each dose performed by group. MANOVA was also administered in ZFD rats + Ex. by dose and baseline for compound group 1 (w/o vehicle if dose level is 0). Binary t-tests for the ZFD group at each time point as well as a binary t-test for the ZFD group for the change from baseline at each time point are performed. Data for the manual von Frey test are analyzed using chi-square analysis for responders. For data from the electric von Frey trial, one-way ANOVA was performed across all groups, followed by group and each dose and ZFD rats + Ex. A MANOVA (~ repeated measures) analysis by baseline is performed for the compound group of 1 (w/o vehicle if the dose level is 0). Binary t-tests of the ZFD group were performed for the ZFD group response at each time point and for the change from baseline at each time point.

cold sore. ZFD rats show a robust response frequency to paw presentation of cold (10° C.) probes. Ex. administered to rats in 10% Trapsol vehicle (in water) given s.c. Compound 1 reduces % response frequency in a dose dependent manner (Table 18-1) ["Control" refers to Sprague-Dawleymarn control rats and "ZFD" refers to Zuker fatty diabetic rats) do]. 3 and 10 mg/kg doses of Ex. Compound 1 significantly reduces the reaction frequency after treatment. Ex. Treatment of the rats with compound i.t. of 1 also significantly reduced the response frequency (%) at 1 and 3 μg doses; At 1 μg the difference from vehicle was significant, while at 3 μg there was a significant difference from vehicle at 1, 2, and 4 h time points (Table 18-2).

Passive von Frey (tactile) ZFD rats show a robust response of paw presentation of passive von Frey filaments, as measured by a reduced threshold for paw avoidance. Ex. administered to rats in 10% Trapsol vehicle (in water) given s.c. Compound 1 reduced the threshold for paw withdrawal in a dose-dependent manner (Table 18-3). Ex. 3 mg/kg dose. Compound 1 significantly normalized the threshold for paw withdrawal, evident at 1 and 2 h after treatment; The 10 mg/kg dose induces significant differences from vehicle at 1, 2, and 4 h time points. These rats were treated with Ex. Treatment with compound i.t. of 1 also significantly normalized the threshold at the 1 μg dose level (Table 18-4).

foot pressure response. ZFD rats show a strong response frequency to paw presentation of mechanical von Frey filaments. Ex. administered to rats in 10% Trapsol vehicle (in water) given s.c. Compound 1 reduced the response frequency (%) in a dose-dependent manner (Table 18-5). Ex. 3 mg/kg dose. Compound 1 significantly reduced the response frequency at 1 and 2 h after treatment; 10 mg/kg significantly improved pain response at 1, 2, 4, and 6 h time points. These rats were treated with Ex. Treatment with compound it of 1 also significantly reduced the response frequency (%) compared to vehicle at 1 μg (2 and 4h) and 3 μg (1, 2, and 4h) (Table 18- 6).

formalin test. s.c. or Ex. Compound 1 had no effect on pain response in the early or late phase of the formalin trial when administered at the end of the study.

In Zuker fatty diabetic rats, a stable and robust nociceptive neuropathic pain response lasting for several months develops. These rats show a significant increase in allodynia, as well as a reduced pain threshold in the tests of the tactile and pressure hyperalgesia assays. s.c. or provided as i.t., Ex. Compound 1, the free base, significantly attenuated the painful neuropathy in all three trials. s.c. and i.t. gave similar results, indicating that the effect is not simply a peripherally mediated effect. Data is Ex. We support the conclusion that the compound of 1 attenuates the painful neuropathic pain response in rats with persistent insulin deficiency diabetes.

Claims (26)

In a patient in need of treatment for chronic and/or neuropathic pain, such as isolated or purified free or salt form (eg, pharmaceutical A method for the treatment of chronic and/or neuropathic pain comprising administering a compound of the formula (I)
Pain is caused by a peripheral neuropathy (e.g., mononeuropathy, plexopathy, neuromyopathy, or polyneuropathy) or is caused by a central neuropathy (e.g., afferent block pain or sympathetic maintenance pain, such as complex regional pain syndrome (CRPS) )), which is caused by:

In the above formula,
R ¹ is H, C _{1- 6} alkyl, -C (O) -OC (R a) (R b) (R c), -C (O) -O-CH 2 -OC (R a) (R b )(R ^c ) or —C(R ⁶ )(R ⁷ )-OC(O)-R ⁸ ;
R ² and R ³ are independently selected from H, D, C _{1- 6} alkyl (e.g., methyl), C _{1- 6} alkoxy (e.g., methoxy), halo (e.g., F), cyano, or selected from hydroxy become;
L is C _{1- 6} alkylene (e.g., ethylene, propylene, or butylene), C _{1- 6} alkoxy (e. G., Propoxy or butoxy), C _{2- 3} alkoxy C _{1 - 3} alkylene (e.g., - _{CH 2 CH 2 OCH 2 -)} , C 1- 6 alkylamino or N- C _{1- 6} alkyl, C _{1- 6} alkylamino (e.g., propylamino, or N- methyl-propyl-amino), C _1-6 alkylthio (e.g. _{, -CH 2 CH 2 CH 2 S-} ), C 1- 6 alkylsulfonyl _{(e.g., -CH 2 CH 2 CH 2 S} (O) 2 - and), and each optionally substituted with one or more R ⁴ moiety;
Each R ⁴ is independently a C _{1- 6} alkyl (e.g., methyl), C _{1- 6} alkoxy (e.g., methoxy), halo (e.g., F), cyano, or is selected from hydroxy;
Z is selected from aryl (eg, phenyl) and heteroaryl (eg, pyridyl, indazolyl, benzimidazolyl, benzisoxazolyl), said aryl or heteroaryl optionally substituted with one or more R ⁴ moieties;
R ⁸ is -C(R ^a )(R ^b )(R ^c ), -OC(R ^a )(R ^b )(R ^c ), or -N(R ^d )(R ^e );
R ^a, R ^b and R ^c are each independently selected from H and C _{1- 24} alkyl;
R ^d and R ^e is selected from each independently selected from H and C _{1- 24} alkyl;
R ⁶ and R ⁷ each independently is selected from H, C _{1- 6} alkyl, carboxy and C _{1- 6} alkoxycarbonyl. 2. A method comprising compounds of formula (I) according to claim 1, wherein R ^{1 is H.} 2. The method of claim 1 wherein R ¹ comprises a C _{1- 6} alkyl, such as methyl A compound of formula I. 2. The method of claim 1, wherein R ¹ is -C(O)-OC(R ^a )(R ^b )(R ^c ), -C(O)-O-CH ₂ -OC(R ^a )(R ^b )( R ^c ) or -C(R ⁶ )(R ⁷ )-OC(O)-R ⁸ . The method according to any one of claims 1 to 4, L is an unsubstituted C _{1- 6} alkylene (e.g., ethylene, propylene, or butylene) or a L is substituted with at least one R ⁴ moiety is C _{1 -} a method comprising a compound of formula (I), wherein the compound is _{6 alkylene (eg ethylene, propylene, or butylene).} 5. The method of any one of claims 1 to 4, wherein L is unsubstituted C _1-6 alkoxy (eg propoxy or butoxy) or L is _{C 1-6} alkoxy substituted with ^{one or more R 4 moieties.} (eg propoxy or butoxy). 7. A method according to any one of claims 1 to 6 comprising compounds of formula I ^{, wherein R 1} , R ² and R ^{3 are each H.} 8. A method according to any one of claims 1 to 7 comprising compounds of formula I, wherein Z is aryl (eg phenyl) ^{optionally substituted with one or more R 4 moieties. 8. The phenyl of any one of claims 1-7, wherein Z is substituted with one R 4} moiety selected from halo (eg, fluoro, chloro, bromo or iodo) and cyano (eg, Z is 4-fluorophenyl, or 4-chlorophenyl, or 4-cyanophenyl). 8. A compound of formula I according to any one of claims 1 to 7, wherein Z is phenyl substituted with one fluoro (eg 2-fluorophenyl, 3-fluorophenyl or 4-fluorophenyl). How to include. 8. Formula I according to any one of claims 1 to 7, wherein Z is heteroaryl (eg pyridyl, indazolyl, benzimidazolyl, benzisoxazolyl) optionally substituted with ^{one or more R 4 moieties} A method comprising a compound. 12. The method of claim 11, wherein said heteroaryl is monocyclic 5 or 6 membered heteroaryl (eg, pyridyl, pyrimidyl, pyrazinyl, thiophenyl, pyrrolyl, thiophenyl, furanyl, imidazolyl, oxazolyl , isoxazolyl, thiazolyl). 12. The method of claim 11, wherein said heteroaryl is a bicyclic 9-membered or 10-membered heteroaryl (eg, indolyl, isoindolyl, benzfuranyl, benzthiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, Benzisoxazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, benzodioxolyl, 2-oxo-tetrahydroquinolinyl). ^{12. The method of claim 11, wherein said heteroaryl is substituted with one R 4} moiety selected from halo (eg, fluoro, chloro, bromo or iodo) and cyano (eg, said heteroaryl is 6-fluoro rho-3-indazolyl, 6-chloro-3-indazolyl, 6-fluoro-3-benzisoxazolyl, or 5-chloro-3-benzisoxazolyl) a method comprising a compound of formula (I). 15. The method according to any one of claims 1 to 14, comprising a compound of formula (I), each independently present in free or pharmaceutically acceptable salt form:

. 16. The method according to any one of claims 1 to 15, comprising a compound of formula I selected from the group consisting of:

. 17. The method of any one of claims 1 to 16, which is present in free or pharmaceutically acceptable salt form.

A method comprising a compound of formula (I) wherein 18. A method according to any one of claims 1 to 17 comprising a compound of formula (I) which is present in the form of a salt, eg in the form of a pharmaceutically acceptable salt. 19. A compound according to any one of claims 1 to 18, wherein the compound of formula (I) is administered in the form of a pharmaceutical composition comprising a compound of formula (I) present in admixture with a pharmaceutically acceptable diluent or carrier. how to be. 20. The method of claim 19, wherein the pharmaceutical composition is a sustained release or delayed release formulation. 21. The method according to claim 19 or 20, wherein the pharmaceutical composition comprises a compound of formula (I) in a polymer matrix. 22. The method according to any one of claims 1-21, wherein the pain is neuropathic pain, eg chronic neuropathic pain. 23. The method of claim 22, wherein the pain is caused by a mononeuropathy (eg, mononeuropathy), such as focal mononeuropathy, pressure mononeuropathy, or sympathetic mononeuropathy (eg, carpal tunnel syndrome); or by polymononeuropathy or polyneuropathy, such as diabetic polyneuropathy; or by drug-induced neurotoxicity (e.g., doxorubicin, etoposide, gemcitabine, ifosfamide, interferon alpha, platinum chemotherapeutic agents (e.g., cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin, phenan) triplatin, picoplatin, satraplatin), or vinca alkaloids (eg, vinblastine, vincristine, vindesine, vinorelbine or vinpocetine), or antiretroviral nucleosides (eg, didanosine, stavudine) , by zalcitabine); or post-herpetic neuralgia (PHN). 24. The method of claim 22 or 23, wherein the patient has previously been treated with another pain relief drug and the patient has not responded adequately to the drug, eg, the patient's pain has not been sufficiently relieved, or the patient has persistent A method of suffering from side effects that interfered with treatment. Use of a compound of formula I as defined in claim 1 in free or pharmaceutically acceptable salt form in the manufacture of a medicament for the treatment of chronic and/or neuropathic pain, wherein the pain is associated with peripheral neuropathy (eg, single neuropathy, plexopathy, neuromyopathy, or polyneuropathy), or by a central neuropathy (eg, afferent block pain or sympathetic maintenance pain, such as complex regional pain syndrome (CRPS)), or The use is caused by fibromyalgia. A compound of formula (I) as defined in claim 1 for use in the treatment of chronic and/or neuropathic pain, wherein the neuropathic pain is characterized by peripheral neuropathy (eg mononeuropathy, plexopathy, neuromyopathy, or polyneuropathy). condition), or by a central neuropathy (eg, afferent block pain or sympathetic maintenance pain, such as complex regional pain syndrome (CRPS)), or by fibromyalgia.